Search

Background and Aim: Patients with Systemic Lupus Erythematosus (SLE) present increased cardiovascular mortality compared to the general population. Few studies have assessed the long-term development and progression of carotid atherosclerotic plaque in SLE patients. Our aim was to investigate the association of clinical and laboratory markers of disease activity and classical cardiovascular risk factors (CVRF) with carotid atherosclerosis development in SLE patients in a prospective 5-year study., Methods and Results: Clinical history and information on principal CVRFs were collected at baseline and after 5 years in 40 SLE patients (36 women, mean age 42 ± 9 years; 14.4 ± 7 years of mean disease duration) and 50 age-matched controls. Carotid Doppler ultrasonography was employed to quantify the atherosclerotic burden at baseline and at follow up. Clinimetrics were applied to assess SLE activity over time (SLEDAI). The association between basal circulating T cell subsets (including CD4 + CCR5 + ; CD4 + CXCR3 + ; CD4 + HLADR + ; CD4 + CD45RA + RO - , CD4 + CD45RO + RA - and their subsets) and atherosclerosis development was evaluated. During the 5-year follow up, 32% of SLE patients, developed carotid atherosclerosis compared to 4% of controls. Furthermore, considering SLEDAI changes over time, patients within the highest tertile were those with increased incidence of carotid atherosclerosis independently of CVRF. In addition, increased levels of CD4 + CCR5 + T cells were independently associated with the development of carotid atherosclerosis in SLE patients., Conclusion: Serial clinical evaluations over time, rather than a single point estimation of disease activity or CVRF burden, are required to define the risk of carotid atherosclerosis development in SLE patients. Specific T cell subsets are associated with long-term atherosclerotic progression and may further be of help in predicting vascular disease progression., (Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aim: Critically discuss the available data, to identify the current gaps and to provide key concepts that will help clinicians in translating the biology of adipokines in the context of atherosclerosis and cardio-metabolic diseases., Data Synthesis: Adipose tissue is nowadays recognized as an active endocrine organ, a function related to the ability to secrete adipokines (such as leptin and adiponectin) and pro-inflammatory cytokines (tumor necrosis factor alpha and resistin). Studies in vitro and in animal models have observed that obesity status presents a chronic low-grade inflammation as the consequence of the immune cells infiltrating the adipose tissue as well as adipocytes. This inflammatory signature is often related to the presence of cardiovascular diseases, including atherosclerosis and thrombosis. These links are less clear in humans, where the role of adipokines as prognostic marker and/or player in cardiovascular diseases is not as clear as that observed in experimental models. Moreover, plasma adipokine levels might reflect a condition of adipokine-resistance in which adipokine redundancy occurs. The investigation of the cardio-metabolic phenotype of carriers of single nucleotide polymorphisms affecting the levels or function of a specific adipokine might help determine their relevance in humans. Thus, the aim of the present review is to critically discuss the available data, identify the current gaps and provide key concepts that will help clinicians translate the biology of adipokines in the context of atherosclerosis and cardio-metabolic diseases., (Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Abdominal obesity and hepatic steatosis are ectopic fat depots associated with Metabolic Syndrome (MetS). Epicardial Fat Thickness (EFT) is a newly discovered one, increasing with obesity, insulin resistance and MetS. Therefore we studied whether different ectopic fat markers, and EFT in particular, are associated with MetS and markers of subclinical cardiovascular disease., Methods and Results: 868 subjects from the PLIC Study were included, EFT, aortic calcifications, carotid Intima-Media Thickness (c-IMT) and echocardiographic parameters were determined by ultrasound; extra-cardiac atherosclerotic lesions were defined in presence of plaques at both carotid and aortic levels. Hepatic steatosis degrees were defined according to a scoring system. Abdominal adiposity was determined using Dual X-ray Absorbimetry (DEXA). Independently from age, women showed higher EFT versus men (4.5 (0.20-9.00) mm vs 4.00 (0.10-8.00) mm, p = 0.013); EFT was thicker in post-menopausal women (independently from hormone-replacement therapy). EFT, liver steatosis and abdominal adiposity increased with MetS (p < 0.001). EFT was the only ectopic fat marker associated with cardiac dysfunction (OR = 1.340 [1.088-1.651 95% C.I., p = 0.006); liver steatosis and EFT were associated with extra-cardiac plaques (OR = 2.529 [1.328-4.819] 95% C.I., p < 0.001 and OR = 1.195 [1.008-1.299] 95% C.I., p = 0.042; respectively). On top of cardiovascular risk factors, only EFT improved the discrimination of subjects with cardiac dysfunction and atherosclerotic plaques., Conclusions: EFT is associated with left ventricular dysfunction and subclinical atherosclerosis. Our data suggest that EFT may represent an additional tool for the stratification of cardiovascular risk., (Copyright © 2015 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aim: Patients with systemic lupus erythematosus (SLE) have a higher prevalence of subclinical atherosclerosis and higher risk of cardiovascular (CV) events compared to the general population. The relative contribution of CV-, immune- and disease-related risk factors to accelerated atherogenesis in SLE is unclear., Methods and Results: Fifty SLE patients with long-lasting disease (mean age 44 ± 10 years, 86% female) and 50 sex- and age-matched control subjects were studied. Common carotid artery intima-media thickness (CCA-IMT) was used as a surrogate marker of atherosclerosis. We evaluated traditional and immune- and disease-related factors, assessed multiple T-cell subsets by 10-parameter-eight-colour polychromatic flow cytometry and addressed the effect of pharmacological therapies on CCA-IMT. In SLE patients, among several cardiometabolic risk factors, only high-density lipoprotein levels (HDL) and their adenosine triphosphate-binding cassette transporter 1 (ABCA-1)-dependent cholesterol efflux capacity were markedly reduced (p < 0.01), whereas the CCA-IMT was significantly increased (p = 0.03) compared to controls. CCA-IMT correlated with systolic blood pressure, low-density lipoprotein (LDL) cholesterol and body mass index (BMI), but not with disease activity and duration. The activated CD4(+)HLA-DR(+) and CCR5(+) T-cell subsets were expanded in SLE patients. Patients under hydroxychloroquine (HCQ) therapy showed lower CCA-IMT (0.62 ± 0.08 vs. 0.68 ± 0.10 mm; p = 0.03) and better risk-factor profile and presented reduced circulating pro-atherogenic effector memory T-cell subsets and a parallel increased percentage of naïve T-cell subsets., Conclusion: HDL represents the main metabolic parameter altered in SLE patients. The increased CCA-IMT in SLE patients may represent the net result of a process in which 'classic' CV risk factors give a continuous contribution, together with immunological factors (CD4(+)HLA-DR(+) T cells) which, on the contrary, could contribute through flares of activity of various degrees over time. Patients under HCQ therapy present a modified metabolic profile, a reduced T-cell activation associated with decreased subclinical atherosclerosis., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background and Aim: Pentraxin 3 (PTX3) is an essential component of the humoral arm of innate immunity and, like C-reactive protein, is independently associated with the risk of developing vascular events. Aim of this study was to investigate, in two large population-based surveys, the Bruneck Study and the PLIC Study, whether PTX3 plasma levels predict the progression of common carotid artery intima-media thickness (CCA-IMT), a surrogate marker of atherosclerosis, in the general population during 5 or 6 years of follow-up., Results: In the Bruneck Study, PTX3 plasma levels did not predict a faster progression of CCA-IMT either in the carotid artery or in the femoral artery. This finding was confirmed in the PLIC Study where subjects within the highest tertile of PTX3 did not show an increased progression of CCA-IMT. PTX3 plasma levels were also not associated with the fastest maximum IMT progression. In summary, in more than 2400 subjects from the general population, PTX3 plasma level is neither an independent predictor of progression of subclinical atherosclerosis in different arterial territories, including carotid and femoral arteries nor of incident cardiovascular events., Conclusion: These findings support the relevance of investigating the predictive value of PTX3 plasma levels only in specific settings, like overt CVD, heart failure or acute myocardial infarction., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Aims: This short review aims at summarizing the current information on Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) structure and function focusing also on the therapeutic possibilities based on the inhibition of this protein., Data Synthesis: PCSK9 has been recently discovered as the third gene involved in autosomal dominant hypercholesterolemia. PCSK9 binds and favors degradation of the low-density lipoprotein receptor (LDLR) and thereby modulates the plasma levels of LDL-cholesterol (LDL-C). Some of the natural occurring PCSK9 mutations increase the protein function (gain of function) and cause hypercholesterolemia, whereas loss of function mutations associate with hypocholesterolemia. Since the loss of a functional PCSK9 in humans is not associated with apparent deleterious effects, this protease is an attractive target for the development of lowering plasma LDL-C agents, either alone or in combination with statins., Conclusion: Inhibition of PCSK9 is emerging as a novel strategy for the treatment of hypercholesterolemia and data obtained from pre-clinical studies show that use of monoclonal antibodies, antisense oligonucleotides and short interfering RNA are effective in reducing LDL-C, clinical studies, accompanied by a better understanding of PCSK9 biology, are now necessary to address whether these new compounds will have a future in clinical practice., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background and Aim: Adiponectin (ADPN) exerts anti-inflammatory and cardio protective effects and is associated with decreased cardiovascular risk, however its role in patients with chronic kidney disease is unclear., Methods and Results: We investigated the correlation between plasma ADPN levels, the progression of CVD and CKD and the inflammatory gene expression profile of peripheral blood mononuclear cells in patients from the NephroPLIC study (a prospective study aimed at addressing the progression of cardiovascular damage in relation to kidney dysfunction). Plasma ADPN levels were directly correlated with age, HDL-C and creatinine, and inversely with BMI, triglycerides and glomerular filtration rate (GFR). Multiple regression analysis identified plasma creatinine and HDL as the independent factors associated with ADPN plasma levels. In peripheral blood mononuclear cells (PBMC), the mRNA expression of MCP-1, CD40, Cox-2, TLR4, PAI-1, TNF alpha, resistin and RAGE was up-regulated in the group with higher GFR and higher ADPN plasma levels compared to that with low GFR and ADPN plasma levels. Patients with similar GFR values showed no differences in the gene expression profile of PBMC although ADPN levels were associated with decreased CRP and IL-6 plasma levels and decreased IMT and heart left ventricular mass., Conclusion: In CKD patients who are not in dialysis ADPN plasma levels are associated with a reduced renal excretory function, but correlate inversely with the determinants of the metabolic syndrome such as glucose, triglycerides and BMI, and directly with HDL. Furthermore, in patients with a similar degree of renal impairment, ADPN plasma levels are associated with a better cardiometabolic profile, despite no significant difference being observed in the gene expression pattern of PBMC., (Copyright 2009 Elsevier B.V. All rights reserved.)

Aim: Dietary cholesterol absorption, endogenous cholesterol synthesis and biliary cholesterol excretion regulate whole body cholesterol balance as a result of biotransformation into bile acids or direct cholesterol excretion. Recent studies have significantly advanced our understanding of intestinal sterol absorption at molecular level. This review concentrates on two major issues: the mechanisms of sterol absorption, and the currently available or experimental drugs that affect this pathway., Data Synthesis: Nuclear hormone receptors, such as the liver X, farnesoid X and retinoid X receptors, regulate the absorption of dietary sterols by modulating the transcription of several genes involved in cholesterol metabolism, The ABC proteins transport dietary cholesterol from enterocytes back to the intestinal lumen, thus limiting the amount of absorbed cholesterol. By means of the same mechanism, ABC transporters also provide an efficient barrier against the absorption of plant sterols. Phytosterols, bile acid sequestrants, ezetimibe and ACAT inhibitors are possible means of affecting these pathways., Conclusion: In addition to providing an insight into the molecular mechanisms of sterol absorption, these recent findings may lead to new therapeutic options for the treatment of hypercholesterolemia. This is particularly true in the case of patients at high risk of coronary artery disease requiring aggressive lipid-lowering therapy combining a statin with drugs affecting cholesterol absorption in order to ensure the optimal management of dyslipidemia.

Background and Aim: Evidence for apoptosis has been found in advanced atherosclerotic lesions, but the factors triggering it are poorly understood. Oxidised low-density lipoproteins (LDLs) are cytotoxic to a variety of cells and induce the apoptosis of smooth muscle cells (SMC), fibroblast, macrophages and endothelial cells in vitro. The aim of this study was to investigate apoptotic cell death in the early phases of aortic atherosclerosis in rabbits, and whether oxidised LDLs colocalize ex vivo with apoptotic cells in atherosclerotic lesions in cholesterol-fed rabbits., Methods and Results: Male albino New Zealand rabbits were fed a standard diet or a diet containing 1.2% cholesterol for 60 days. The aortic arch of each animal was sectioned and stained with antibodies against SMC, endothelial cells, macrophages and oxidised LDLs or for proteins involved in apoptotic pathways such as Fas, Bax, Bcl2, and caspase 3. The nuclei in adjacent sections were stained with Hoechst 33258, TUNEL and for the proliferating cell nuclear antigen (PCNA). Early atherosclerotic lesions were characterised by intimal thickening and the presence of SMC and macrophages. The percentage of apoptotic cells, calculated as the ratio of TUNEL-positive nuclei to total nuclei was 32.6 +/- 3.73% in the lesions and 55.9 +/- 2.36% in the endothelium. As it has been reported that nuclei undergoing active gene transcription can be TUNEL positive, we evaluated the percentage of PCNA-positive cells, which proved to be 45.2 +/- 4.68% along the endothelium and 22.3 +/- 2.7% in the intima. The true percentage of apoptotic cells was therefore about 10% in both cases. Fas, Bax and caspase3 signals were mainly located in the endothelium and SMC proximal to the lumen, whereas Bcl2 colocalized with macrophages and SMC deeper in the lesions. Abundant oxidised LDL epitopes were detected in areas of lipid accumulation and along the endothelium, mainly in the areas in which TUNEL and PCNA-positive cells were localised., Conclusions: Our findings may be taken as ex vivo indications of an apoptotic and proliferating role of oxidised LDLs as previously shown in vitro, and may at least partially account for the endothelial dysfunction that can be rapidly induced by hypercholesterolemia.