Key Role In Cardiovascular Diseases Research Articles

Abstract # 3142 Association between complicated grief and inflammation among bereaved adults

The loss of a spouse is a highly stressful life event and bereavement is associated with an increased risk of death from cardiovascular disease (CVD). Given inflammation’s key role in CVD, it is an essential mechanism through which bereaved individuals may experience heightened risk for CVD. Complicated grief symptoms are prognostic of both mental and physical health issues, including cardiovascular problems, and engender negative emotions that may amplify inflammation. This study explored the mechanisms linking inflammation and CVD to complicated grief among 100 bereaved participants using the Inventory of Complicated Grief to assess ”caseness” of complicated grief (CG). Inflammation was measured using in vitro stimulated cytokine secretion by T cells. After controlling for medication use income, alcohol use, time since bereavement, BMI, age, and comorbid conditions, bereaved individuals with CG had higher levels of several pro-inflammatory cytokines. Specifically, complicated grief was associated with higher levels of the pro-inflammatory cytokines IL-6 ( M CG = 5.07, SD CG = 0.38, M NCG = 4.25, SD NCG = 0.24, p =.03), TNF-alpha ( M CG = 6.89, SD CG = 0.43, M NCG = 6.24, SD NCG = 0.22, p =.03), and IFN-gamma ( M CG = 8.50, SD CG = 0.49, M NCG = 7.76, SD NCG = 0.27, p =.03). CG did not significantly predict IL17-A, IL-2, or any other chemokines (CCL5, CXCL10, CCL2). This is the first study to demonstrate the association between CG and inflammation. .

Towards more specific treatment for diabetic dyslipidemia.

Treatment of diabetic dyslipidemia is necessary because of its impact on cardiovascular disease, which is the leading cause of death in patients with diabetes. In the past, standard treatment of diabetic dyslipidemia focused only on correcting lipids. Although this remains the mainstay of treatment, because new antihyperglycemic treatments reduce cardiovascular events with minimal effect on dyslipidemia, a new approach is both timely and relevant. LDL-lowering remains the focus of treatment for diabetic dyslipidemia, especially in patients with both diabetes and cardiovascular disease (CVD). Higher intensity statin therapy or lower LDL cholesterol goals are recommended in these patients. Combination therapy, especially with ezetimibe, fibrates, bile acid sequestrants, PCSK9 inhibitors and omega 3 fatty acids should be considered along with selected new agents to reduce glycemia. As diabetic dyslipidemia plays a key role in CVD, aggressive treatment is indicated. New research targets include apo-CIII and lipoprotein(a) [Lp(a)]. In addition, new antihyperglycemic therapy is changing diabetes care and altering treatment guidelines. The most recent American Diabetes Association Standards of Care has expanded its recommendations for people with CVD and diabetes, suggesting that medications validated to improve cardiac health should be strongly considered.

Inhibition of 5-Hydroxytryptamine Receptor 2B Reduced Vascular Restenosis and Mitigated the β-Arrestin2-Mammalian Target of Rapamycin/p70S6K Pathway.

BackgroundAs a monoamine neurotransmitter, 5‐hydroxytryptamine (5‐HT) or serotonin modulates mood, appetite, and sleep. Besides, 5‐HT also has important peripheral functions. 5‐HT receptor 2B (5‐HT2BR) plays a key role in cardiovascular diseases, such as pulmonary arterial hypertension and cardiac valve disease. Percutaneous intervention has been used to restore blood flow in occlusive vascular disease. However, restenosis remains a significant problem. Herein, we investigated the role of 5‐HT2BR in neointimal hyperplasia, a key pathological process in restenosis.Methods and ResultsThe expression of 5‐HT2BR was upregulated in wire‐injured mouse femoral arteries. In addition, BW723C86, a selective 5‐HT2BR agonist, promoted the injury response during restenosis. 5‐HT and BW723C86 stimulated migration and proliferation of rat aortic smooth muscle cells. Conversely, LY272015, a selective antagonist, attenuated the 5‐HT–induced smooth muscle cell migration and proliferation. In vitro study showed that the promigratory effects of 5‐HT2BR were mediated through the activation of mammalian target of rapamycin (mTOR)/p70S6K signaling in a β‐arrestin2–dependent manner. Inhibition of mammalian target of rapamycin or p70S6K mitigated 5‐HT2BR–mediated smooth muscle cell migration. Mice with deficiency of 5‐HT2BR showed significantly reduced neointimal formation in wire‐injured arteries.ConclusionsThese results demonstrated that activation of 5‐HT2BR and β‐arrestin2–biased downstream signaling are key pathological processes in neointimal formation, and 5‐HT2BR may be a potential target for the therapeutic intervention of vascular restenosis.

CX3CL1/CX3CR1 Axis Contributes to Angiotensin II-Induced Vascular Smooth Muscle Cell Proliferation and Inflammatory Cytokine Production.

Angiotensin II (Ang II) dysregulation has been determined in many diseases. The CX3CL1/CX3CR1 axis, which has a key role in cardiovascular diseases, is involved in the proliferation and inflammatory cytokine production of vascular smooth muscle cells (VSMCs). In this study, we aim to explore whether Ang II has a role in the expression of CX3CL1/CX3CR1, thus contributing to the proliferation and pro-inflammatory status of VSMCs. Cultured mouse aortic VSMCs were stimulated with 100nmol/L of Ang II, and the expression of CX3CR1 was assessed by western blot. The results demonstrated that Ang II significantly up-regulated CX3CR1 expression in VSMCs and induced the production of reactive oxygen species (ROS) and the phosphorylation of p38 MAPK. Inhibitors of NADPH oxidase, ROS, and AT1 receptor significantly reduced Ang II-induced CX3CR1 expression. Targeted disruption of CX3CR1 by transfection with siRNA significantly attenuated Ang II-induced VSMC proliferation as well as down-regulated the expression of proliferating cell nuclear antigen (PCNA). Furthermore, CX3CR1-siRNA suppressed the effect of Ang II on stimulating Akt phosphorylation. Besides, the use of CX3CR1-siRNA decreased inflammatory cytokine production induced by Ang II treatment. Our results indicate that Ang II up-regulates CX3CR1 expression in VSMCs via NADPH oxidase/ROS/p38 MAPK pathway and that CX3CL1/CX3CR1 axis contributes to the proliferative and pro-inflammatory effects of Ang II in VSMCs.

Segmental arterial stiffness in relation to B-type natriuretic peptide with preserved systolic heart function.

BackgroundCentral arterial stiffness has been shown to play a key role in cardiovascular disease. However, evidence regarding such arterial stiffness from various arterial segments in relation to B-type natriuretic peptide (BNP) remains elusive.MethodsA total of 1255 participants (47.8% men; mean age: 62.6 ± 12.3 [SD] years) with preserved left ventricular function (ejection fraction ≥50%) and ≥1 risk factors were consecutively studied. Arterial pulse wave velocity (PWV) by automatic device (VP-2000; Omron Healthcare) for heart-femoral (hf-PWV), brachial-ankle (ba-PWV), and heart-carotid (hc-PWV) segments were obtained and related to BNP concentrations (Abbott Diagnostics, Abbott Park, IL, USA).ResultsSubjects in the highest hf-PWV quartile were older and had worse renal function and higher blood pressure (all P < 0.05). Elevated PWV (m/s) was correlated with elevated BNP (pg/ml) (beta coefficient = 19.3, 12.4, 5.9 for hf-PWV, ba-PWV, hc-PWV respectively, all p < 0.05). After accounting for clinical co-variates and left ventricle mass index (LVMI), both hf-PWV and ba-PWV were correlated with higher BNP (beta coefficient = 8.3, 6.4 respectively, P < 0.01 for each). Adding both hf-PWV and ba-PWV to LVMI significantly expanded ROC in predicting abnormal BNP>100 pg/ml (both P < 0.01), but only hf-PWV presented significant integrated discrimination improvement to predict risk for BNP concentrations (0.7%, P = 0.029).ConclusionA significant segmental PWV associated with biomarker BNP concentrations suggests that arterial stiffness is associated with myocardial damage.

A novel ruthenium (II)-derived organometallic compound, TQ-6, potently inhibits platelet aggregation: Ex vivo and in vivo studies

Arterial thrombosis plays a key role in cardiovascular diseases. Hence, developing more effective antithrombotic agents is necessary. We designed a ruthenium (II)-derived complex, [Ru(η6-cymene)2-(1H-benzoimidazol-2-yl)-quinoline Cl]BF4 (TQ-6), as a new antiplatelet drug. TQ-6 (0.3 µM) exhibited extremely strong inhibitory activity against platelet aggregation, Src, and Syk phosphorylation stimulated by agonists in human platelets. In collagen-activated platelets, TQ-6 also inhibited ATP-release, [Ca+2]i, P-selectin expression, FITC-PAC-1 binding, and hydroxyl radical formation, as well as the phosphorylation of phospholipase Cγ2, protein kinase C, mitogen-activated protein kinases, and Akt. Neither FITC-JAQ1 nor FITC-triflavin binding or integrin β3 phosphorylation stimulated by immobilized fibrinogen were diminished by TQ-6. Furthermore, TQ-6 had no effects in cyclic nucleotide formation. Moreover, TQ-6 substantially prolonged the closure time in whole blood, increased the occlusion time of thrombotic platelet plug formation and bleeding time in mice. In conclusion, TQ-6 has a novel role in inhibiting platelet activation through the inhibition of the agonist receptors-mediated inside-out signaling such as Src-Syk-PLCγ2 cascade and subsequent suppression of granule secretion, leading to disturb integrin αIIbβ3-mediated outside-in signaling, and ultimately inhibiting platelet aggregation. Therefore, TQ-6 has potential to develop as a therapeutic agent for preventing or treating thromboembolic disorders.

Expansion of CD8+ T cells lacking the IL-6 receptor α chain in patients with coronary artery diseases (CAD)

Background and aimsThe pathogenesis of coronary artery disease (CAD) is closely associated with chronic inflammatory processes. CD8+ T cells are a key participant in the pathogenesis of atherosclerosis, the major cause of CAD; however, it remains unclear which CD8+ T-cell subset is responsible. We investigated the immunological features of CD8+ T cells expressing low and high levels of the IL-6 receptor α chain (IL-6Rα), a cytokine known to play a key role in cardiovascular diseases. MethodsThe expression of IL-6Rα on CD8+ T cells and its association with plasma levels of soluble components of the IL-6/IL-6Rs as well as with clinical parameters were analyzed using FACS analysis and ELISA of CAD patients and age-matched healthy controls (HCs). Immunological characteristics of CD8+ T cells expressing low and high levels of IL-6Rα (CD8+IL-6Rαlow or high) were examined by in vitro culture and intracellular FACS analysis. ResultsCAD patients had higher frequencies of circulating CD8+IL-6Rαlow effector memory (EM) T cells compared with HCs (median frequency; 74.59% vs. 60.09%, p = 0.0158). Expanded CD8+IL-6Rαlow T cells positively correlated with the frequency of senescent, cytotoxic CD8+CD57+ T cells (r = 0.6655, p < 0.0001) and plasma IL-6 level (r = 0.3995, p = 0.0432) in CAD patients. Loss of IL-6Rα expression on CD8+ T cells was induced by the combination of IL-6 and IL-15 with accompanying TCR-independent proliferation (p = 0.0101). Moreover, these CD8+IL-6Rαlow T cells had features of type 1 cytotoxic CD8+ T cells. ConclusionsOur findings suggest the possible involvement of expanded CD8+IL-6Rαlow EM T cells in CAD through their pro-inflammatory and highly cytotoxic capacities.

Compensatory Effect between Aortic Stiffening and Remodelling during Ageing.

The arterial tree exhibits a complex spatio-temporal wave pattern, whose healthy behaviour depends on a subtle balance between mechanical and geometrical properties. Several clinical studies demonstrated that such a balance progressively breaks down during ageing, when the aorta stiffens and remodels by increasing its diameter. These two degenerative processes however, have different impacts on the arterial wave pattern. They both tend to compensate for each other, thus reducing the detrimental effect they would have had if they had arisen individually. This remarkable compensatory mechanism is investigated by a validated multi-scale model, with the aim to elucidate how aortic stiffening and remodelling quantitatively impact the complex interplay between forward and reflected backward waves in the arterial network. We focus on the aorta and on the pressure at the ventricular-aortic interface, which epidemiological studies demonstrate to play a key role in cardiovascular diseases.

Can selenium supplementation modify oxidative stress in-vitro? A role for selenium supplementation in the prevention of cardiovascular disease

Background Two thirds of the UK population are either overweight or obese (body mass index (BMI) 25-29.9 and >30 kg/m respectively) and are typically characterised by systemic oxidative stress (OS); deemed to play a key role in cardiovascular disease (CVD) development. OS results from chronically high reactive oxidative species (ROS) formation and reduced antioxidant status. OS plays a key role in CVD development by initiating atherosclerosis (fatty plaque accumulation within the arterial walls); therefore obese individuals are at increased risk of atherosclerosis development. Increased monocyte ROS generation instigates atherosclerotic plaque formation by increasing the recruitment, binding and transmigration of monocytes across arterial endothelial cells and into the arterial wall. An increased dietary antioxidant intake or up-regulation of endogenous antioxidant enzymes may counteract this OS state and therefore lower CVD risk. Selenium is an essential dietary micronutrient incorporated within the catalytic site of endogenous antioxidant Glutathione Peroxidase (GPx) enzymes, which protect cells from OS and consequent cell damage. There is, however, a lack of knowledge concerning the effect of selenium supplementation in an OS state representative of sedentary overweight/obese individuals. The aim of this work was to investigate the ability of selenium supplementation to modify monocyte cell viability/ROS production under OS. Materials and methods U937 monocyte cells were supplemented with sodium selenite (Na2SeO3; 100nM or 200nM) or not and cultured for 48 hours at 37°C. Paraquat (100mM) and S-Nitroso-Nacetyl-DL-penicillamine (10mM) (PQ/SNAP) were added to the cells to induce OS. Cell viability was assessed via MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay while ROS production was determined by Flow Cytometry using the reagent CM-H2DC-FDA.

Association of serum uric acid levels to inflammation biomarkers and endothelial dysfunction in obese prepubertal children

High serum uric acid (SUA) levels are present in patients with metabolic syndrome (MetS), when the latter is associated with endothelial dysfunction, inflammation, and hypertension. This increase in SUA levels may have a key role in cardiovascular diseases. We aim to quantify the differences in inflammation biomarkers, endothelial dysfunction, and parameters associated with MetS in obese prepubertal children compared to non-obese children, and determine if there is a relationship between uric acid levels and these variables. A cross-sectional study was carried out on obese children (6-9 yr old). The study included 43 obese children and the same number of non-obese children (control group), matched by age and sex. SUA, C-reactive protein (CRP), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1), glucose, insulin, lipid profile, and blood pressure were all measured. SUA levels, CRP, and sICAM-1 were significantly higher in obese children. In the obese group, SUA levels showed a positive correlation with body mass index (BMI), insulin, homeostasis model assessment for insulin resistance (HOMA-IR), CRP, IL-6, sICAM-1, and triglycerides (TGs), and correlated negatively with high-density lipoprotein cholesterol (HDL-C) and Apo-AI, but not with Apo-B. When adjusted for age, sex, and creatinine, it was noted that SUA levels are independent predictive factors for sICAM-1, CRP, and IL-6. Inflammation biomarkers, endothelial dysfunction, and parameters associated with MetS are elevated in obese prepubertal children and correlate to uric acid levels.

Phosphodiesterase type 4 blockade prevents platelet-mediated neutrophil recruitment at the site of vascular injury.

Platelet-neutrophil interactions play a key role in cardiovascular disease and inflammatory processes. Src family kinases mediate P-selectin glycoprotein ligand-1-Mac-1 cross talk necessary for firm platelet-neutrophil adhesion. Because Src family kinase activity can be regulated by cAMP-dependent pathways, in this work, we evaluated the role of phosphodiesterases in the signaling events that are required to sustain platelet-neutrophil interactions and neutrophil recruitment at the site of vascular injury. In neutrophils exposed to P-selectin, selective phosphodiesterase 4 (PDE4) inhibition prevented Src family kinase-mediated phosphorylation of the proline-rich tyrosine kinase 2 on Tyr579/Tyr580. The effects of PDE4 inhibition required protein kinase A, likely through protein kinase A-mediated activation of COOH-terminal Src kinase, a major negative regulator of Src family kinases. PDE4, but not other phosphodiesterase inhibitors, reduced platelet-neutrophil conjugates as well as neutrophil firm adhesion on spread platelets under flow conditions. The effect of PDE4 inhibition on neutrophil adhesion was primarily mediated by downregulation of P-selectin-induced activation of Mac-1. In a murine model of endovascular injury, selective inhibition of PDE4 significantly reduced neutrophil recruitment at the site of vascular damage. This study identifies PDE4 as a central node in the signaling network that mediates platelet-neutrophil adhesion and suggests that pharmacological inhibition of PDE4 may represent a novel therapeutic avenue for the treatment of cardiovascular disease.

Identification of a Missense Variant in LNPEP that Confers Psoriasis Risk

Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To further advance gene discovery, we extended our genome-wide association study data set of 1,139 cases and 2,234 controls and replicated two independent cohorts of 7,200 cases and 10,491 controls. We identified the missense variant rs2303138 (p.Ala763Thr) within the LNPEP gene associated with psoriasis (Pcombined=1.83 × 10(-13), odds ratio=1.16) and validated four previously reported genes: IL28RA, NFKBIA, TRAF3IP2, and CARD14 (9.74 × 10(-11)P9.37 × 10(-5)), which confirmed the involvement of the nuclear factor-κB signaling pathway in psoriasis pathogenesis. LNPEP, also named insulin-responsive aminopeptidase, was identified as an angiotensin IV receptor. Protein function prediction suggested that this missense variant of LNPEP was most likely deleterious. Expression analysis showed that LNPEP was significantly downregulated in psoriatic lesions compared with the control skin (P=1.44 × 10(-6)) and uninvolved patient skin (P=2.95 × 10(-4)). Pathway analysis indicated that LNPEP was involved in the renin-angiotensin system, which also has a key role in cardiovascular disease and diabetes. These results provided genetic evidence that psoriasis might share common mechanisms with hypertension and diabetes, which was consistent with clinical observations. Our study identified a genetic susceptibility factor and provided genetic evidence of insight into psoriasis pathogenesis with the involvement of the renin-angiotensin system pathway.

Influence of sex differences on microRNA gene regulation in disease

Sexual dimorphism is observed in most human diseases. The difference in the physiology and genetics between sexes can contribute tremendously to the disease prevalence, severity, and outcome. Both hormonal and genetic differences between males and females can lead to differences in gene expression patterns that can influence disease risk and course. MicroRNAs have emerged as potential regulatory molecules in all organisms. They can have a broad effect on every aspect of physiology, including embryogenesis, metabolism, and growth and development. Numerous microRNAs have been identified and elucidated to play a key role in cardiovascular diseases, as well as in neurological and autoimmune disorders. This is especially important as microRNA-based tools can be exploited as beneficial therapies for disease treatment and prevention. Sex steroid hormones as well as X-linked genes can have a considerable influence on the regulation of microRNAs. However, there are very few studies highlighting the role of microRNAs in sex biased diseases. This review attempts to summarize differentially regulated microRNAs in males versus females in different diseases and calls for more attention in this underexplored area that should set the basis for more effective therapeutic strategies for sexually dimorphic diseases.

MicroRNAs and Atherosclerosis

MicroRNAs (miRNAs) are small, ~22 nucleotide (nt) sequences of RNA that regulate gene expression at posttranscriptional level. These endogenous gene expression inhibitors were primarily described in cancer but recent exciting findings have also demonstrated a key role in cardiovascular diseases (CVDs), including atherosclerosis. MiRNAs control endothelial cell (EC), vascular smooth muscle cell (VSMC), and macrophage functions, and thereby regulate the progression of atherosclerosis. MiRNA expression is modulated by different stimuli involved in every stage of atherosclerosis, and conversely miRNAs modulates several pathways implicated in plaque development such as cholesterol metabolism. In the present review, we focus on the importance of miRNAs in atherosclerosis, and we further discuss their potential use as biomarkers and therapeutic targets in CVDs.

Proteomic Identification of Matrix Metalloproteinase Substrates in the Human Vasculature

Matrix metalloproteinases (MMPs) play a key role in cardiovascular disease, in particular aneurysm formation and plaque rupture. Surprisingly, little is known about MMP substrates in the vasculature. We used a proteomics approach to identify vascular substrates for 3 MMPs, 1 of each of the 3 major classes of MMPs: Human arteries were incubated with MMP-3 (a member of stromelysins), MMP-9 (considered a gelatinase), and MMP-14 (considered a member of the collagenases and of the membrane-bound MMPs). Candidate substrates were identified by mass spectrometry based on increased release from the arterial tissue on digestion, spectral evidence for proteolytic degradation after gel separation, and identification of nontryptic cleavage sites. Using this approach, novel candidates were identified, including extracellular matrix proteins associated with the basement membrane, elastic fibers (emilin-1), and other extracellular proteins (periostin, tenascin-X). Seventy-four nontryptic cleavage sites were detected, many of which were shared among different MMPs. The proteomics findings were validated by immunoblotting and by digesting recombinant/purified proteins with exogenous MMPs. As proof-of-principle, results were related to in vivo pathology by searching for corresponding degradation products in human aortic tissue with different levels of endogenous MMP-9. The application of proteomics to identify MMP targets is a new frontier in cardiovascular research. Our current classification of MMPs based on few substrates is an oversimplification of a complex area of biology. This study provides a more comprehensive assessment of potential MMP substrates in the vasculature and represents a valuable resource for future investigations.

Modulation of Angiotensin II Effects in Vascular Smooth Muscle Cells by microRNAs

Angiotensin II (AngII)‐mediated vascular smooth muscle cell (VSMC) dysfunction plays a key role in cardiovascular diseases. However, the role of microRNAs (miRNAs) in this process is unclear. We used small RNA deep sequencing to profile AngII‐regulated miRNAs and evaluated their role in rat VSMC. Bioinformatics analysis showed that the predicted targets of AngII‐responsive miRNAs can modulate biological processes relevant to cardiovascular diseases. Further studies showed time‐ and dose‐dependent upregulation of miR‐32 and miR‐212 cluster (miR‐132/212) by AngII. We identified phosphatase and tensin homolog (PTEN) as a novel target of miR‐132 and showed miR‐132 mediates monocyte chemoattractant protein‐1 (MCP‐1) induction in VSMC partly via PTEN repression. miR‐132 overexpression also enhanced cyclic AMP‐response element binding protein (CREB) phosphorylation whereas its inhibition attenuated AngII‐induced CREB activation. Furthermore, miR‐132 induction by AngII required CREB activation, demonstrating a positive feedback loop. Notably, aortas from AngII‐infused mice showed higher levels of miR‐132/212 and MCP‐1. In addition, microarray analysis combined with RT‐QPCR revealed that a subset of genes downregulated by AngII was miR‐132 predicted targets, and they are associated with AngII functions. These results suggest that miR132/212 fine‐tunes and amplifies AngII actions in VSMC.

Control of eotaxin-1 expression and release by resveratrol and its metabolites in culture human pulmonary artery endothelial cells.

Population studies suggest that moderate red wine intake correlates with reduced risk of cardiovascular disease (CVD); cardioprotection may attribute to consumption of red wine polyphenol resveratrol. Since inflammation plays a key role in CVD, we investigated modulation of inflammation by resveratrol and its metabolites by determining the expression and release of chemokine, eotaxin-1, in cultured human pulmonary artery endothelial cells (HPAEC) treated with proinflammatory cytokines IL-13 and TNF-α. Up-regulation of eotaxin-1 gene expression by IL-13 or TNF-α was confirmed by RT-PCR, by reporter assays using eotaxin-1 gene promoter constructs, and by the changes in transcriptional factors STAT6 and NF-κB. Exposure to resveratrol suppressed IL-13 and TNF-α induced eotaxin-1 gene expression as well as attenuated the eotaxin-1 promoter activity, in coordination with inhibition of expression of JAK-1, reduction in phosphorylated-STAT6 and decreased p65 subunit of NF-κB. In addition, quantitative determination of eotaxin-1 release using enzyme-linked immunosorbent assay (ELISA) showed increased eotaxin-1 release in response to treatment by IL-13 and TNF-α, which was effectively inhibited by resveratrol. Whether resveratrol metabolites affected eotaxin-1 was also tested; piceatannol showed potency similar to resveratrol. We propose that control of eotaxin-1 expression and release by proinflammatory cytokines in HPAEC may be considered as an in vitro model for screening and discovering polyphenols with anti-inflammatory activities and cardioprotective potentials.

Clinical Summaries

Clinical Summaries

Relationship between epicardial adipose tissue adipocyte size and MCP-1 expression

Adipocyte size has been associated to increase in inflammatory cytokines expression that can be related to the cardiovascular risk of obesity. Epicardial adipose tissue (EAT) was discovered to play a key role in cardiovascular diseases by producing several inflammatory adipokines. We sought to study whether EAT and subcutaneous adipose tissue (SAT) mean adipocyte sizes are related to the expression of adipokines in patients with cardiovascular diseases. We collected EAT, SAT and blood samples from 22 patients aged 70.9 (s.d. 10.3) undergoing heart surgery. Monocyte chemoattractant protein (MCP)-1, interleukin (IL)-10 and tumor necrosis factor (TNF)-α were analyzed by real time RT-PCR, ELISA or immunohistochemistry. Hematoxylin–eosin staining was used for adipocyte area calculations. Adipocyte size is negatively correlated to MCP-1 expression ( r = −0.475; p = 0.034) in EAT and positively correlated in SAT ( r = 0.438; p = 0.047). These trends persisted after stratification for sex and coronary artery disease (CAD), but only the relationship between EAT MCP-1 and adipocyte size reached statistical significance in the larger group of men with CAD. We have observed that SAT adipocyte size is correlated to BMI ( r = 0.601; p = 0.003); whereas only a non-statistically significant trend was observed in EAT. IL-10 and TNF-α expression were not associated to adipocyte size in EAT nor SAT. Secondarily, we found that EAT IL-10 expression is higher in patients with CAD. These results suggest that adipocyte size is a negative determinant of MCP-1 expression in EAT and a positive determinant in SAT. These data might partly explain the different implications of EAT and SAT in cardiovascular diseases.

A systematic review of the effect of TNF-α antagonists on lipid profiles in patients with rheumatoid arthritis

Atherosclerosis plays a key role in cardiovascular disease in patients with rheumatoid arthritis (RA). Although therapy with TNF-alpha antagonists has resulted in dramatic improvement in the prognosis of RA, its effects on circulatory lipids are unclear. We conducted a systematic review of the literature to summarize the available evidence on lipid profile modification in patients with RA treated with TNF-alpha antagonists, with extensive searches in PubMed, the Cochrane Collaboration database (Central), and SCOPUS. Twenty-four observational studies met the inclusion criteria; 12 included only patients with RA treated with infliximab and three, patients with RA treated with adalimumab. The other nine included a mix of patients with various rheumatic diseases, or receiving one of several TNF-alpha antagonists. Eleven studies found a statistically significant increase in total cholesterol (TC) and high-density lipoprotein (HDL); six of 20 found significant increases in triglycerides (TG). Four of 13 studies found a statistical increase in low-density lipoprotein. No major changes were observed for ApoB/ApoA1 ratios. A small trend to increased TC was observed in patients receiving TNF-alpha antagonists, mostly due to an increase in HDL. There was a small trend to increased TG, and no changes in ApoB/ApoA1 ratio. The clinical impact of these findings is unclear, and further studies are needed to clarify the role of these lipid changes on cardiovascular morbidity in RA.