Glycolipid Metabolic Disorders, Metainflammation, Oxidative Stress, and Cardiovascular Diseases: Unraveling Pathways.

Glycolipid metabolic disorders (GLMDs) are various metabolic disorders resulting from dysregulation in glycolipid levels, consequently leading to an increased risk of obesity, diabetes, liver dysfunction, neuromuscular complications, and cardiorenal vascular diseases (CRVDs). In patients with GLMDs, excess caloric intake and a lack of physical activity may contribute to oxidative stress (OxS) and systemic inflammation. This study aimed to review the connection between GLMD, OxS, metainflammation, and the onset of CRVD. GLMD is due to various metabolic disorders causing dysfunction in the synthesis, breakdown, and absorption of glucose and lipids in the body, resulting in excessive ectopic accumulation of these molecules. This is mainly due to neuroendocrine dysregulation, insulin resistance, OxS, and metainflammation. In GLMD, many inflammatory markers and defense cells play a vital role in related tissues and organs, such as blood vessels, pancreatic islets, the liver, muscle, the kidneys, and adipocytes, promoting inflammatory lesions that affect various interconnected organs through their signaling pathways. Advanced glycation end products, ATP-binding cassette transporter 1, Glucagon-like peptide-1, Toll-like receptor-4, and sphingosine-1-phosphate (S1P) play a crucial role in GLMD since they are related to glucolipid metabolism. The consequences of this is system organ damage and increased morbidity and mortality.

Lipoproteínas ricas en triglicéridos y riesgo cardiovascular residual / Triglyceride rich lipoproteins and residual cardiovascular risk / Lipoproteínas ricas em triglicerídeos e risco cardiovascular residual / Reconocimiento a la trayectoria del Prof. Dr. Juan Miguel Castagnino†

Resumen Una vasta evidencia científica de resultados de ensayos clínicos, preclínicos, epidemiológicos y genéticos, mostraron una asociación causal entre el aumento de triglicéridos (TG), lipoproteínas ricas en TG (LRT) y sus remanentes para la enfermedad cardiovascular aterosclerótica (ECA). La acumulación de LRT circulantes puede explicar, en parte, el riesgo cardiovascular residual que se observa en pacientes eficazmente tratados para reducir sus niveles de LDL; sin embargo, persiste el riesgo de ECA. Es imprescindible que en el estudio del perfil lipídico se considere la determinación o estimación de estas lipoproteínas, sumada a la medida de TG plasmáticos. El objetivo de la presente revisión fue actualizar el conocimiento acerca de los niveles incrementados de TG, de LRT y sus remanentes, brindar alternativas para su determinación y comprender los mecanismos que involucran a las LRT en el desarrollo acelerado de la aterosclerosis. La actualización de los diferentes parámetros asociados al aumento de TG y sus valores de corte o límites de decisión clínica según la clasificación del riesgo de ECA para cada paciente, permitirá el rediseño de un informe de resultados que será de gran utilidad para el médico y el paciente con respecto a las conductas preventivas y terapéuticas de la ECA.

Abstract Vast scientific evidence from clinical, preclinical, epidemiological, and genetic trial results show a causal association between increased triglycerides (TG), TG-rich lipoproteins (TRL), and their remnants for atherosclerotic cardiovascular disease (ASCVD). The accumulation of circulating LRT may explain, in part, the residual cardiovascular risk observed in patients successfully treated to reduce their LDL levels, however, the risk of ASCVD still persists. It is essential that in the assessment of the lipid profile, the determination or estimation of these lipoproteins be considered, added to the measurement of plasmatic TG. The objective of this review is to update the knowledge about the increased levels of TG, LRT and their remnants, proprovide alternatives for their determination and understand the mechanisms that involve LRT in the accelerated development of atherosclerosis. Updating the different parameters associated with increased TG and their cut-off values or clinical decision limits according to the ASCVD risk classification for each patient will allow for the redesign of a results report that will be very useful for the physician and the patient regarding the preventive and therapeutic behaviours of the ASCVD.

Resumo Vastas evidências científicas de resultados de ensaios clínicos, pré-clínicos, epidemiológicos e genéticos mostraram uma associação causal entre o aumento de triglicerídeos (TG), lipoproteínas ricas em TG (LRT) e seus remanescentes para doença cardiovascular aterosclerótica (DCA). O acúmulo de LRT circulante pode explicar, em parte, o risco cardiovascular residual observado em pacientes tratados de maneira eficaz para reduzir seus níveis de LDL, no entanto, o risco de DCA persiste. É fundamental que no estudo do perfil lipídico seja considerada a determinação ou estimativa dessas lipoproteínas, somada à dosagem de TG plasmáticos. O objetivo desta revisão foi atualizar o conhecimento sobre os níveis aumentados de TG, LRT e seus remanescentes, fornecer alternativas para sua determinação e compreender os mecanismos que envolvem as LRT no desenvolvimento acelerado da aterosclerose. A atualização dos diferentes parâmetros associados ao aumento de TG, e seus valores de corte ou limites de decisão clínica de acordo com a classificação do risco de DCE para cada paciente, permitirá o redesenho de um relatório de resultados que será muito útil para o médico e o paciente quanto às condutas preventivas e terapêuticas da DCE.

Aerobic Exercise Training Reduces Atherogenesis Induced by Low-Sodium Diet in LDL Receptor Knockout Mice.

This study investigated the efficacy of aerobic exercise training (AET) in the prevention of dyslipidemia, insulin resistance (IR), and atherogenesis induced by severe low-sodium (LS) diet. LDL receptor knockout (LDLR KO) mice were fed a low-sodium (LS) (0.15% NaCl) or normal-sodium (NS; 1.27% NaCl) diet, submitted to AET in a treadmill, 5 times/week, 60 min/day, 15 m/min, for 90 days, or kept sedentary. Blood pressure (BP), plasma total cholesterol (TC) and triglyceride (TG) concentrations, lipoprotein profile, and insulin sensitivity were evaluated at the end of the AET protocol. Lipid infiltration, angiotensin II type 1 receptor (AT1), receptor for advanced glycation end products (RAGE), carboxymethyllysine (CML), and 4-hydroxynonenal (4-HNE) contents as well as gene expression were determined in the brachiocephalic trunk. BP and TC and gene expression were similar among groups. Compared to the NS diet, the LS diet increased vascular lipid infiltration, CML, RAGE, 4-HNE, plasma TG, LDL-cholesterol, and VLDL-TG. Conversely, the LS diet reduced vascular AT1 receptor, insulin sensitivity, HDL-cholesterol, and HDL-TG. AET prevented arterial lipid infiltration; increases in CML, RAGE, and 4-HNE contents; and reduced AT1 levels and improved LS-induced peripheral IR. The current study showed that AET counteracted the deleterious effects of chronic LS diet in an atherogenesis-prone model by ameliorating peripheral IR, lipid infiltration, CML, RAGE, 4-HNE, and AT1 receptor in the intima-media of the brachiocephalic trunk. These events occurred independently of the amelioration of plasma-lipid profile, which was negatively affected by the severe dietary-sodium restriction.

Failure Analysis of TEVG's II: Late Failure and Entering the Regeneration Pathway.

Tissue-engineered vascular grafts (TEVGs) are a promising alternative to treat vascular disease under complex hemodynamic conditions. However, despite efforts from the tissue engineering and regenerative medicine fields, the interactions between the material and the biological and hemodynamic environment are still to be understood, and optimization of the rational design of vascular grafts is an open challenge. This is of special importance as TEVGs not only have to overcome the surgical requirements upon implantation, they also need to withhold the inflammatory response and sustain remodeling of the tissue. This work aims to analyze and evaluate the bio-molecular interactions and hemodynamic phenomena between blood components, cells and materials that have been reported to be related to the failure of the TEVGs during the regeneration process once the initial stages of preimplantation have been resolved, in order to tailor and refine the needed criteria for the optimal design of TEVGs.

Accelerated atherosclerosis in rheumatoid arthritis: a systematic review.

Background: Rheumatoid arthritis (RA) is a highly prevalent, chronic inflammatory condition of the synovial joints that affects approximately 1% of the global population. The pathogenesis of RA is predominantly inflammatory in nature, thereby accelerating the co-occurrence of other immunoinflammatory conditions such as atherosclerosis. Apart from traditional cardiovascular risk factors, RA patients possess a multitude of other factors that predispose them to early atherosclerotic disease. The aim of this systematic review is to assess the prevalence of premature atherosclerosis in RA patients and elucidate the role that proinflammatory cytokines, RA-related autoantibodies, and endothelial dysfunction play in the pathophysiology of RA-mediated atherosclerosis. We also discussed novel biomarkers that can be used to predict early atherosclerosis in RA and current guidelines used to treat RA. Methods: This review followed the PRISMA guidelines to select and analyze relevant articles. A literature search for articles was performed on February 25, 2022, through three research databases including PubMed, ProQuest, and ScienceDirect. The query used to identify relevant publications was "Rheumatoid arthritis and atherosclerosis" and the search duration was set from 2012-2022. Relevant articles were selected based on the inclusion and exclusion criteria. Results: Our initial search generated 21,235 articles. We narrowed our search according to the inclusion and exclusion criteria. After assessing eligibility based on the full content of the articles, 73 articles were ultimately chosen for this review. Conclusion: There is an increased prevalence of accelerated atherosclerosis among RA patients. We found evidence to explain the role of proinflammatory cytokines, RA-related autoantibodies, and endothelial dysfunction in the pathophysiology RA-mediated atherosclerosis. Therapies targeting either the inflammatory load or traditional CV risk-factors seem to improve vascular outcomes in RA patients. Novel markers of atherosclerosis in RA may be useful in predicting premature atherosclerosis and serve as new targets for therapeutic intervention.

Betanin as a multipath oxidative stress and inflammation modulator: a beetroot pigment with protective effects on cardiovascular disease pathogenesis.

Oxidative stress is a common physiopathological condition enrolled in risk factors for cardiovascular diseases. Individuals in such a redox imbalance status present endothelial dysfunctions and inflammation, reaching the onset of heart disease. Phytochemicals are able to attenuate the main mechanisms of oxidative stress and inflammation and should be considered as supportive therapies to manage risk factors for cardiovascular diseases. Beetroot (Beta vulgaris L.) is a rich source of bioactive compounds, including betanin (betanidin-5-O-ß-glucoside), a pigment displaying the potential to alleviate oxidative stress and inflammantion, as previously demonstrated in preclinical trials. Betanin resists gastrointestinal digestion, is absorbed by the epithelial cells of intestinal mucosa and reaches the plasma in its active form. Betanin displays free-radical scavenger ability through hydrogen or electron donation, preserving lipid structures and LDL particles while inducing the transcription of antioxidant genes through the nuclear factor erythroid-2-related factor 2 and, simultaneously, suppressing the pro-inflammatory nuclear factor kappa-B pathways. This review discusses the anti-radical and gene regulatory cardioprotective activities of betanin in the pathophysiology of endothelial damage and atherogenesis, the main conditions for cardiovascular disease. In addition, betanin influences on these multipath cellular signals and aiding in reducing cardiovascular disorders is proposed.

Native Low-Density Lipoproteins Act in Synergy with Lipopolysaccharide to Alter the Balance of Human Monocyte Subsets and Their Ability to Produce IL-1 Beta, CCR2, and CX3CR1 In Vitro and In Vivo: Implications in Atherogenesis.

Increasing evidence has demonstrated that oxidized low-density lipoproteins (oxLDL) and lipopolysaccharide (LPS) enhance accumulation of interleukin (IL)-1 beta-producing macrophages in atherosclerotic lesions. However, the potential synergistic effect of native LDL (nLDL) and LPS on the inflammatory ability and migration pattern of monocyte subpopulations remains elusive and is examined here. In vitro, whole blood cells from healthy donors (n = 20) were incubated with 100 µg/mL nLDL, 10 ng/mL LPS, or nLDL + LPS for 9 h. Flow cytometry assays revealed that nLDL significantly decreases the classical monocyte (CM) percentage and increases the non-classical monocyte (NCM) subset. While nLDL + LPS significantly increased the number of NCMs expressing IL-1 beta and the C-C chemokine receptor type 2 (CCR2), the amount of NCMs expressing the CX3C chemokine receptor 1 (CX3CR1) decreased. In vivo, patients (n = 85) with serum LDL-cholesterol (LDL-C) >100 mg/dL showed an increase in NCM, IL-1 beta, LPS-binding protein (LBP), and Castelli's atherogenic risk index as compared to controls (n = 65) with optimal LDL-C concentrations (≤100 mg/dL). This work demonstrates for the first time that nLDL acts in synergy with LPS to alter the balance of human monocyte subsets and their ability to produce inflammatory cytokines and chemokine receptors with prominent roles in atherogenesis.

AGEs-Induced and Endoplasmic Reticulum Stress/Inflammation-Mediated Regulation of GLUT4 Expression and Atherogenesis in Diabetes Mellitus.

In recent decades, complex and exquisite pathways involved in the endoplasmic reticulum (ER) and inflammatory stress responses have been demonstrated to participate in the development and progression of numerous diseases, among them diabetes mellitus (DM). In those pathways, several players participate in both, reflecting a complicated interplay between ER and inflammatory stress. In DM, ER and inflammatory stress are involved in both the pathogenesis of the loss of glycemic control and the development of degenerative complications. Furthermore, hyperglycemia increases the generation of advanced glycation end products (AGEs), which in turn refeed ER and inflammatory stress, contributing to worsening glycemic homeostasis and to accelerating the development of DM complications. In this review, we present the current knowledge regarding AGEs-induced and ER/inflammation-mediated regulation of the expression of GLUT4 (solute carrier family 2, facilitated glucose transporter member 4), as a marker of glycemic homeostasis and of cardiovascular disease (CVD) development/progression, as a leading cause of morbidity and mortality in DM.

Leukocyte-Endothelium Interaction Is Associated with Fat Mass in Children.

OBJECTIVE: To study leukocyte-endothelium interaction, a measure of the initial phase of atheromatosis, in children with overweight or obesity. STUDY DESIGN: A prospective study was conducted in 77 children aged 7-16 years; 47 were children with overweight/obesity and 30 were normal weight. Polymorphonuclear neutrophils (PMNs) and peripheral blood mononuclear cells were isolated from venous blood samples and the interaction of leukocytes over a monolayer of human umbilical vein endothelial cells was analyzed using flow chamber microscopy. The variables studied included leukocyte rolling velocity, rolling flux, and adhesion to endothelial cells. These were compared between children with overweight/obesity and control children. Correlation between the measures of leukocyte-endothelium interaction and anthropometric and biochemical variables was evaluated. RESULTS: In comparison with normal weight children, the PMNs and peripheral blood mononuclear cells of the overweight/obesity group showed a reduction in rolling velocity (P = .000 and P = .001, respectively) and an increase in rolling flux (P = .001 and P = .004), and adhesion (P = .003 and P = .002). The homeostasis model of insulin resistance was correlated inversely with rolling velocity and positively with rolling flux in PMNs. C-reactive protein was correlated positively with rolling flux and adhesion in both types of leucocytes. Fat mass index was correlated with all measures of leukocyte-endothelial interaction and proved to be the main predictor of leukocyte adhesion in the multiple regression analysis (P = .001 for PMNs and P = .006 for peripheral blood mononuclear cells). CONCLUSIONS: Excess fat mass in children is related to the activation of the leukocyte-endothelium interaction, potentially contributing to the development of atherosclerosis.

Neutrophil-to-lymphocyte ratio and its relation with pro-inflammatory mediators, visceral adiposity and carotid intima-media thickness in population with obesity.

BACKGROUND: Atherosclerosis represents a cardiovascular risk. Chronic inflammation is a key factor for atherogenic progression. Neutrophil-to-lymphocyte ratio (NLR) has been proposed as a novel biomarker for cardiovascular risks. We aimed to explore whether NLR was related to surrogate pro-atherogenic promoters driving atherogenic progression, as measured by carotid intima-media thickness (CIMT). STUDY DESIGN: Thirty-one patients with obesity candidates for bariatric surgery were recruited from Centro Médico Nacional "20 de Noviembre", ISSSTE, Mexico City. The results are part of the "CROP" study (NCT03561987). NLR was calculated from routine complete blood count, and its relation with plasma pro-inflammatory mediators (hsCRP, TNF-α and IL-1ß), adipokines (adiponectin and leptin), adiposity markers (visceral adipose tissue [VAT] determined from CT scan image and VAT individual adipocyte area at histological sample) and CIMT were determined. RESULTS: Neutrophil-to-lymphocyte ratio correlated with hsCRP (Spearman's r = 0.70 [95% CI 0.46 to 0.85], P < 0.01), TNF-α (r = 0.69 [0.44 to 0.84], P < 0.0001) and adiponectin (r = -0.69 [-0.84 to -0.45], P < 0.03), as well as with VAT individual adipocyte area (r = 0.64 [0.37 to 0.81], P < 0.0001) and with VAT area (r = 0.43; [0.07 to 0.68], P < 0.01). Leptin and adiponectin showed further independent association with higher NLR (multivariate regression analysis OR 7.9 [95% CI 1.1 to 56.2] P = 0.03 and 0.1 [0.01 to 1.0] P = 0.05, respectively). Moreover, NLR distribution significantly varied between subgroups divided according to progressive CIMT (P = 0.05); whereas adiponectin and VAT adipocyte area associated with CIMT > 0.9 mm (univariate analysis OR 0.1 [0.01 to 1.0] P = 0.05 and 13.1 [1.4 to 126.3] P = 0.03, respectively). CONCLUSION: Neutrophil-to-lymphocyte ratio was related to pro-inflammatory, adiposity biomarkers and progressive subclinical atherogenesis.

The attempt to demolish the science and practice of preventive cardiovascular medicine. Part I. Addendum to the positioning around the diagnosis and treatment of dyslipidemias of ANCAM and the joint group of associated medical societies / El intento de demoler la ciencia y la práctica de la medicina cardiovascular preventiva. Parte I. Addendum al posicionamiento en torno al diagnóstico y tratamiento de las dislipidemias de la ANCAM y del grupo conjunto de sociedades médicas asociadas

Abstract: This manuscript is an addendum to the positioning around the diagnosis and treatment of dyslipidemias of ANCAM and the joint group of associated medical societies, already published. It is the first part of a wider reflection aimed on refute several of the theses and arguments of a group of clinicians and researchers who question the validity of the "cholesterol hypothesis", the usefulness and safety of statins and the most modern inhibitors of proprotein convertase of subtilisin/kexin type 9 (iPCSK9,) and the role of saturated fatty acids consumed in the usual diet in the atherosclerotic risk. This iconoclastic point of view is dangerous insofar as it undermines the scaffolding that supports the primary and secondary prevention of atherosclerosis. In this section of the manuscript, only the cholesterol hypothesis is discussed. The data of comparative zoology are reviewed, and several experimental animal models are analyzed, both supporting the link between cholesterol and the appearance and evolution of atherosclerotic lesions. The methodology and the results of the Study of the 7 Countries are defended and are exposed the numerous epidemiological, pathological, clinical and interventional evidences, which in our opinion give a solid sustenance to the cholesterol hypothesis. Based on this knowledge it is criticized the LDL cholesterol values currently considered adequate. Furthermore, the so-called residual risk is considered, as well as the conflicting evidence about the usefulness of statins in elderly patients.

Resumen: Este manuscrito es un apéndice del posicionamiento en torno al diagnóstico y tratamiento de las dislipidemias de la ANCAM y el grupo de las sociedades médicas asociadas, previamente publicado. Es la primera parte de un trabajo más amplio enfocado a refutar varias de las tesis y argumentos de un grupo de clínicos e investigadores que ponen en duda la validez de la "hipótesis del colesterol", la utilidad y seguridad de las estatinas y los más modernos inhibidores de la proproteína convertasa de la subtilisina/kexina tipo 9 (iPCSK9) y el papel de los ácidos grasos saturados consumidos en la dieta habitual en el riesgo ateroscleroso. Este punto de vista iconoclástico es peligroso porque socava el andamiaje que soporta la prevención primaria y secundaria de la aterosclerosis. En esta primera sección del manuscrito, se discute sólo la hipótesis del colesterol. Se revisan los datos de zoología comparada y se analizan varios modelos animales de experimentación, que apoyan la liga entre el colesterol y la aparición y evolución de las lesiones aterosclerosa. Se defienden la metodología y los resultados del estudio de los 7 países y se exponen las numerosas evidencias epidemiológicas, patológicas, clínicas e intervencionistas, que a nuestro juicio dan un sustento sólido a la hipótesis del colesterol. Se critican también, en base a ese conocimiento, los valores de colesterol LDL actualmente considerados adecuados, a la vez que se discute el llamado riesgo residual y las evidencias conflictivas acerca de la utilidad de las estatinas en pacientes ancianos.

Atherosclerosis and inflammation: overview and updates.

The concept that inflammation participates pivotally in the pathogenesis of atherosclerosis and its complications has gained considerable attention, but has not yet entered clinical practice. Experimental work has elucidated molecular and cellular pathways of inflammation that promote atherosclerosis. The recognition of atherogenesis as an active process rather than a cholesterol storage disease or a repository of calcium has highlighted some key inflammatory mechanisms. For example, mononuclear phagocytes contribute to all stages of this disease, illustrating the link between inflammation and atherosclerosis. From a clinical perspective, harnessing inflammation may now help target therapeutics, change guidelines, and enter daily practice. Multiple lines of incontrovertible evidence have proven a causal role for low-density lipoprotein (LDL) cholesterol in atherosclerosis, and we have highly effective tools for lowering LDL, consequently reducing events. Yet, even with intense LDL reduction, events still occur. Inflammation can explain some of this residual risk. An anti-inflammatory intervention has now proven capable of improving outcomes in individuals well treated with LDL-lowering agents. A suite of trials are now pursuing anti-inflammatory therapies in this context. Assessment and treatment of residual inflammatory risk are poised to provide new inroads into preventive cardiology. This brief review aims to explore the potential mechanisms underlying the association of inflammation and atherogenesis, and their clinical consequences.

Immune-Mediated Inflammation Promotes Subclinical Atherosclerosis in Recent-Onset Psoriatic Arthritis Patients without Conventional Cardiovascular Risk Factors.

Studies on the inflammatory burden in recent-onset psoriatic arthritis (PsA) patients without conventional cardiovascular risk factors (CVRFs) are not available. This preliminary study focuses on cardiovascular risk in cutaneous psoriasis (CPs) and recent-onset PsA patients. Blood biochemistry (glucose, cholesterol, uric acid, lipid profile and apolipoprotein B) was analyzed using standard kits. Proatherogenic inflammation markers, C-reactive protein (CRP) and interleukin-6 (IL-6), and endothelial activators monocyte chemoattractant protein-1 (MCP-1) and soluble intercellular adhesion molecule-1 (sICAM-1), were determined by enzyme-linked immunosorbent assay. Ultrasound images allowed measuring carotid intima-media thickness (cIMT). Our study first shows an increase in cIMT, and in serum levels of sICAM-1 and CRP in recent-onset PsA patients not presenting conventional CVRFs over the non-medicated time-period, from disease diagnosis to the beginning of pharmacological treatment, compared with healthy subjects. The outcome highlights the importance of monitoring serum level of sICAM1, CRP, and cIMT, and the value of primary prevention in psoriatic patients even with no history of cardiovascular events.

Flaxseed oil rich in omega-3 protects aorta against inflammation and endoplasmic reticulum stress partially mediated by GPR120 receptor in obese, diabetic and dyslipidemic mice models.

The "first hit" to atherogenesis is driven by toll-like receptor 4, endoplasmic reticulum stress and ultimately metabolic dysfunction. In this study, we hypothesized that a flaxseed oil-enriched diet (FS) abolishes these inflammatory signaling pathway and restore metabolic homeostasis by activating the fatty acid receptor GPR120 in aorta of obese mice. Glucose homeostasis was assessed by GTT and ITT; lipidomics was performed using a Hybrid Ion Trap-Orbitrap Mass Spectrometer; serum lipids were measured using colorimetric assays; GPR120 and infiltrating macrophages were analyzed by immunofluorescence; protein immunoprecipitation and gene expression were evaluated by Western blot and RT-PCR, respectively. There were no differences in body weight and food intake between the groups from both strains (Swiss and LDLr-KO mice). GTT and cholesterol levels were improved by FS in both mice models. Lipidomics showed an increase in ω3 (C18:3) content, meanwhile stearic acid (C18:0) was not detected in endothelial tissue in response to FS. Moreover, FS markedly decreased pro-inflammatory (IL-1ß, TNF-α, pIκBα, pIKKß) and unfolded protein response markers (ATF6 and GRP78) in aorta. In Swiss mice, GPR120 was partially involved in the ω3-mediated anti-inflammatory actions, disrupting TLR4 pathway, but not in LDLr-KO mice. Partial replacement of dietary saturated by unsaturated ω3 fatty acids contributes to inhibition of cardiovascular risk markers, pro-inflammatory cytokines and ER stress sensors and effectors in the aorta. However, downregulation of inflammation is not mediated by arterial GPR120 activation.

Subclinical atherogenesis in patients with mild psoriasis: A role for IL-6? / Aterogênese subclínica em pacientes com psoríase leve: um papel para IL-6?

Summary Introduction: A link of psoriasis with subclinical atherosclerosis has been postulated and cytokine network might intermediate this association. Few data are available in patients with mild psoriasis. We evaluated carotid intima-media thickness (cIMT) in drug-free psoriatic individuals and controls. In parallel, we searched for associations of cIMT with disease activity indexes and serum interleukins (IL) in psoriatic patients. Method: An experienced radiologist performed the cIMT analyses. Cytokine concentrations were assessed by flow cytometry. Disease activity was evaluated based on psoriasis area and severity index (PASI) as well as body surface area (BSA). Results: Sixty-five (65) patients and 64 controls were studied. Mean age of patients (50.9 years) did not differ from controls (p=0.362). A low PASI and BSA (< 10) prevailed (69.2% and 56.9%, respectively). Median levels of IL-12p70, TNF-α, IL-1β and IL-10 were significantly lower in cases than in controls (adjusted p<0.05), while IL-6 and IL-8 medians did not differ between groups (adjusted p>0.05). Smoking habit and diabetes mellitus predominated in cases (p=0.002). An altered cIMT (≥ 0.9 mm) was more frequent in cases than in controls (23.8% versus 8.5%, adjusted p=0.045). Mean cIMT was higher in cases with a borderline significance (p=0.057). cIMT scores did not correlate to PASI (rs=0.066; p=0.250) or BSA (rs=0.175; p=0.185), but did correlate significantly with serum IL-6 (rs=0.26; p=0.005). Conclusion: Subclinical atherosclerosis was more frequent in patients with mild psoriasis than controls. cIMT in psoriatic individuals correlated with serum IL-6, pointing to an eventual proatherogenic role of IL-6 in these patients. Newer studies should clarify the connection of atherogenesis with cytokines in psoriasis.

Resumo Introdução: Foi postulada uma ligação entre psoríase e aterosclerose subclínica. A rede de citocinas pode intermediar essa associação. Poucos dados estão disponíveis em pacientes com psoríase leve. Avaliamos a espessura íntima-média carotídea (cIMT) em psoriáticos e controles livres de medicação. Paralelamente, pesquisamos a associação de cIMT com os índices de atividade de doença e interleucinas séricas (IL) em pacientes com psoríase. Método: Um radiologista experiente procedeu à análise do cIMT. As concentrações de citocinas foram avaliadas por citometria de fluxo. A atividade da doença foi avaliada pelo índice de gravidade (PASI) e pela área de superfície corporal (BSA). Resultados: Sessenta e cinco (65) pacientes e 64 controles foram estudados. A idade média dos pacientes (50,9 anos) não diferiu dos controles (p=0,362). PASI e BSA baixos (< 10) prevaleceram (69,2% e 56,9%, respectivamente). As medianas de IL-12p70, TNF-α, IL-1β e IL-10 foram significativamente menores nos casos do que nos controles (p<0,05 ajustado), enquanto as medianas de IL-6 e IL-8 não diferiram nos grupos (p>0,05 ajustado). Tabagismo e diabetes mellitus predominaram nos casos (p=0,002). Um cIMT alterado (≥ 0,9 mm) foi mais frequente nos casos do que nos controles (23,8% versus 8,5%, p=0,045 ajustado). A média de cIMT foi maior nos casos com significância borderline (p=0,057). Os escores de cIMT não se correlacionaram com o PASI (rs=0,066; p=0,250) ou o BSA (rs=0,175; p=0,185), mas se correlacionaram significativamente com a IL-6 sérica (rs=0,26; p=0,005). Conclusão: A aterosclerose subclínica foi mais frequente em pacientes com psoríase leve do que nos controles. Em psoriáticos, cIMT correlacionou-se com níveis de IL-6 no soro, apontando para um eventual papel pró-aterogênico para a IL-6 nesses pacientes. Novos estudos devem esclarecer a ligação da aterogênese com citocinas na psoríase.

Pro-atherogenic mediators and subclinical atherogenesis are related to epicardial adipose tissue thickness in patients with cardiovascular risk.

Objective To evaluate the relationship between pro-atherogenic biomarkers and epicardial adipose tissue (EAT) thickness in patients with cardiovascular risk factors. Methods Plasma nitric oxide (NO), soluble intercellular adhesion molecule-1 and malondialdehyde (MDA) levels, EAT thickness, flow-mediated dilation (FMD) and carotid intima media thickness (CIMT) were determined in patients aged >18 years who were referred for echocardiography for heart ischemia or non-ischemic diseases. Cardiovascular risk factors (Framingham score [FS] ≥ 20) were weighted. Results Hypertension, dyslipidaemia and type 2 diabetes mellitus were prevalent (≥55% of 40 patients). Patients with FS ≥ 20 ( n = 21) showed significantly higher EAT and CIMT values. Globally, MDA, CIMT, age, waist circumference, high-density lipoprotein cholesterol (HDL-C) and FS were associated with EAT thickness. EAT was significantly associated with NO in patients with FS ≥ 20. Significant differences in EAT thickness were found between patients stratified by NO value, FMD, age, smoking status, dyslipidaemia, type 2 diabetes mellitus and FS. An EAT-associated atherogenic risk (CIMT ≥ 1 mm) model was statistically significant when MDA and type 2 diabetes mellitus were included. Conclusion EAT thickness was associated with MDA, CIMT, age, waist circumference, HDL-C and FS globally, but with NO only in patients with FS≥20. EAT may be used to identify vascular damage stage, possibly influenced by MDA and type 2 diabetes mellitus.

Nikolai Anichkov y los cien años de la hipótesis sobre el colesterol y la aterogénesis / Nikolai Anichkov and one hundred years of the hypothesis about cholesterol and atherogenesis

The relationship of cholesterol to atherogenesis already fulfilled one hundred years. The merit of this important discovery is attributed to a Russian military doctor, Nikolai Anichkov, who using rabbits as experimental model, was able to show the accumulation of "lipoids" when he fed animals with a diet rich in cholesterol. His experimental observations were criticized by many researchers, since he used an animal that is not carnivorous, so it was an inappropriate model. Anichkov published very few scientific articles, and all of them in Russian language. Only in 1933 he could make public his work to the Western world by publishing a review on his scientific work in English. Was only in 1984 when the scientific community recognized the merit of his research, which was pioneer in the understanding that we have today about the relationship of artherogenesis and cholesterol.

La relación del colesterol con la aterogénesis ya cumplió cien años. El mérito de este importante descubrimiento lo tiene un médico militar ruso Nikolai Anichkov, quien utilizando conejos como modelo experimental, pudo demostrar la acumulación de "lipoides" cuando los alimentaba con una dieta rica en colesterol. Sus observaciones fueron criticadas por numerosos investigadores ya que utilizaba un animal que no es carnívoro, por lo cual era un modelo inadecuado. Anichkov publicó muy pocos trabajos científicos y todos ellos en idioma ruso. Solo en 1933 pudo hacer público su trabajo al mundo occidental al publicar en inglés una revisión sobre su trabajo científico. Tardíamente, en 1984, se reconoció por parte de la comunidad científica el mérito de su investigación, la que fue pionera en la comprensión que tenemos hoy día sobre la enfermedad arterioesclerótica y el colesterol.

Circulating early biomarkers of atherogenesis in participants of the Longitudinal Study of Adult Health (ELSA-Brasil) without diabetes or cardiovascular disease

ABSTRACT Objective Our aim was to describe the distribution of selected biomarkers according to age and sex, adjusted for HOMA-IR and adiposity, in a subset of middle-aged individuals of Brazilian Longitudinal Study of Adult Health-ELSA without diabetes mellitus or CVD. Subjects and methods This cross-sectional study was conducted in 998 participants of the ELSA-Brasil without diabetes and/or cardiovascular disease. In addition to the traditional risk factors, several biomarkers concentrations were compared according to sex, age groups (35-44; 45-54 yrs) and HOMA-IR tertiles. Linear regression was used to examine independent associations of sex and age with selected novel biomarkers, adjusted for body adiposity and HOMA-IR. Results Fifty-five percent were women. Men had higher mean values of body mass index, waist circumference, blood pressure, plasma glucose, HOMA-IR, worse lipid profile and higher E-selectin and lower leptin concentrations than women; while women had higher levels of HDL-cholesterol and leptin than men. Mean values of waist circumference, systolic BP, plasma glucose and apolipoprotein B (Apo B) increased with age in both sexes. Leptin and E-selectin concentrations increased across HOMA-IR tertiles. Independent associations of Apo B with age were found only in male sex, while of leptin with body mass index and HOMA-IR, and of E-selectin with HOMA-IR in both sexes. Conclusions In conclusion, our data indicate age, sex, adiposity and, consequently, insulin resistance, influence circulating levels of Apo B, leptin and E-selectin, suggesting that those aspects should be taken into consideration when assessing these parameters for research or clinical purposes in individuals at relatively low cardiometabolic risk.