Galectin-3 Is Associated with Cardiovascular Events in Post-Acute Coronary Syndrome Patients with Type-2 Diabetes.

INTRODUCTION: Type-2 diabetes mellitus (T2DM) is associated with early and severe atherosclerosis. However, few biomarkers can predict cardiovascular events in this population. METHODS: We followed 964 patients with coronary artery disease (CAD), assessing plasma levels of galectin-3, monocyte chemoattractant protein-1 (MCP-1), and N-terminal fragment of brain natriuretic peptide (NT-proBNP) at baseline. The secondary outcomes were acute ischemia and heart failure or death. The primary outcome was the combination of the secondary outcomes. RESULTS: Two hundred thirty-two patients had T2DM. Patients with T2DM showed higher MCP-1 (144 (113-195) vs. 133 (105-173) pg/mL, p = 0.006) and galectin-3 (8.3 (6.5-10.5) vs. 7.8 (5.9-9.8) ng/mL, p = 0.049) levels as compared to patients without diabetes. Median follow-up was 5.39 years (2.81-6.92). Galectin-3 levels were associated with increased risk of the primary outcome in T2DM patients (Hazard ratio (HR) 1.57 (1.07-2.30); p = 0.022), along with a history of cerebrovascular events. Treatment with clopidogrel was associated with lower risk. In contrast, NT-proBNP and MCP-1, but not galectin-3, were related to increased risk of the event in nondiabetic patients (HR 1.21 (1.04-1.42); p = 0.017 and HR 1.23 (1.05-1.44); p = 0.012, respectively), along with male sex and age. Galectin-3 was also the only biomarker associated with the development of acute ischemic events and heart failure or death in T2DM patients, while, in nondiabetics, MCP-1 and NT-proBNP, respectively, were related to these events. CONCLUSION: In CAD patients, galectin-3 plasma levels are associated with cardiovascular events in patients with T2DM, and MCP-1 and NT-proBNP in those without T2DM.

Predictive and diagnostic biomarkers for gestational diabetes and its associated metabolic and cardiovascular diseases.

Gestational diabetes mellitus (GDM) is defined as the presence of high blood glucose levels with the onset, or detected for the first time during pregnancy, as a result of increased insulin resistance. GDM may be induced by dysregulation of pancreatic ß-cell function and/or by alteration of secreted gestational hormones and peptides related with glucose homeostasis. It may affect one out of five pregnancies, leading to perinatal morbidity and adverse neonatal outcomes, and high risk of chronic metabolic and cardiovascular injuries in both mother and offspring. Currently, GDM diagnosis is based on evaluation of glucose homeostasis at late stages of pregnancy, but increased age and body-weight, and familiar or previous occurrence of GDM, may conditionate this criteria. In addition, an earlier and more specific detection of GDM with associated metabolic and cardiovascular risk could improve GDM development and outcomes. In this sense, 1st-2nd trimester-released biomarkers found in maternal plasma including adipose tissue-derived factors such as adiponectin, visfatin, omentin-1, fatty acid-binding protein-4 and retinol binding-protein-4 have shown correlations with GDM development. Moreover, placenta-related factors such as sex hormone-binding globulin, afamin, fetuin-A, fibroblast growth factors-21/23, ficolin-3 and follistatin, or specific micro-RNAs may participate in GDM progression and be useful for its recognition. Finally, urine-excreted metabolites such as those related with serotonin system, non-polar amino-acids and ketone bodies, may complete a predictive or early-diagnostic panel of biomarkers for GDM.

Liver Cirrhosis From Chronic Hypervitaminosis A Resulting in Liver Transplantation: A Case Report.

Herein we report a case of liver dysfunction caused by consumption of vitamin A supplements leading to liver transplantation. The patient was a 48-year-old male with a medical history of congenital ichthyosiform erythroderma in treatment with vitamin A until 12 years of age, at which point he discontinued the supplements because he had developed ascites. Liver cirrhosis was diagnosed as secondary to hypervitaminosis A on the basis of histologic examination of liver biopsy and the absence of other potential causes of chronic liver disease. Despite interruption of administration of vitamin A, the patient continued to deteriorate over the years, with development of portal hypertension signs. His medical conditions were aggravated with the development of hepatic insufficiency manifested by refractory ascites, renal insufficiency, and severe encephalopathy and he underwent orthotopic liver transplantation, followed by disappearance of all signs of portal hypertension. This case highlights the need to take a careful history of consumption of vitamin A when evaluating a patient with liver failure.

Intraoperative Portal Vein Flow > 123 mL/min Per 100 g Predicts a Better Survival of Patients After Liver Transplantation.

OBJECTIVE: To assess the importance of intraoperative portal vein flow measurement during liver transplantation in relation to postoperative complications and graft and patient survival. MATERIALS AND METHODS: Retrospective review including 291 patients who had all the information and covering a period of 10 years (2007-2017). Using a receiver operating characteristic curve, a cut-off point that would have the greatest impact on the probability of being alive at 5 years was established. In relation to this value, 2 groups were formed (low and high flow) and demographic variables, intraoperative variables, postoperative complications, and graft and patient survival were compared. RESULTS: A portal flow of 123 mL/min per100 g of liver tissue was established (area under the curve = 0.58), obtaining a low-flow (n = 129) and a high-flow group (n = 162). The 2 groups were similar in their preoperative characteristics, except for a higher proportion of preoperative ascites, a higher Model for End-Stage Liver Disease score and a lower weight of donors in the high-flow group. The arterial and portal flows were significantly higher in the high-flow group. In the postoperative period, the high-flow group presented a higher rate of ascites. The 5-year survival rate of patients was significantly higher in the high-flow group (76% vs 84%, P = .03). CONCLUSIONS: Patients undergoing liver transplantation with an intraoperative portal vein flow measurement >123 mL/min per 100 g present a greater 5-year survival rate.

Sitagliptin improved glucose assimilation in detriment of fatty-acid utilization in experimental type-II diabetes: role of GLP-1 isoforms in Glut4 receptor trafficking.

BACKGROUND: The distribution of glucose and fatty-acid transporters in the heart is crucial for energy consecution and myocardial function. In this sense, the glucagon-like peptide-1 (GLP-1) enhancer, sitagliptin, improves glucose homeostasis but it could also trigger direct cardioprotective actions, including regulation of energy substrate utilization. METHODS: Type-II diabetic GK (Goto-Kakizaki), sitagliptin-treated GK (10 mg/kg/day) and wistar rats (n = 10, each) underwent echocardiographic evaluation, and positron emission tomography scanning for [18F]-2-fluoro-2-deoxy-D-glucose (18FDG). Hearts and plasma were isolated for biochemical approaches. Cultured cardiomyocytes were examined for receptor distribution after incretin stimulation in high fatty acid or high glucose media. RESULTS: Untreated GK rats exhibited hyperglycemia, hyperlipidemia, insulin resistance, and plasma GLP-1 reduction. Moreover, GK myocardium decreased 18FDG assimilation and diastolic dysfunction. However, sitagliptin improved hyperglycemia, insulin resistance, and GLP-1 levels, and additionally, enhanced 18FDG uptake and diastolic function. Sitagliptin also stimulated the sarcolemmal translocation of the glucose transporter-4 (Glut4), in detriment of the fatty acyl translocase (FAT)/CD36. In fact, Glut4 mRNA expression and sarcolemmal translocation were also increased after GLP-1 stimulation in high-fatty acid incubated cardiomyocytes. PI3K/Akt and AMPKα were involved in this response. Intriguingly, the GLP-1 degradation metabolite, GLP-1(9-36), showed similar effects. CONCLUSIONS: Besides of its anti-hyperglycemic effect, sitagliptin-enhanced GLP-1 may ameliorate diastolic dysfunction in type-II diabetes by shifting fatty acid to glucose utilization in the cardiomyocyte, and thus, improving cardiac efficiency and reducing lipolysis.

Sun exposure influences the prognostic power of components of mineral metabolism in patients with coronary artery disease.

BACKGROUND AND AIM: Calcidiol (vitamin D metabolite) plasma levels vary with sun exposure (SE). However, it is not known if SE influences its prognostic ability. We have studied the effect of SE on plasma levels of the components of mineral metabolism (calcidiol, fibroblast growth factor-23 [FGF-23], parathormone [PTH], and phosphate [P]) and on their prognostic value in patients with coronary artery disease (CAD). METHODS AND RESULTS: We studied prospectively 704 patients with stable CAD. Clinical variables and baseline calcidiol, FGF-23, PTH, and P plasma levels were assessed. We divided the population in two subgroups, according to the period of plasma extraction: High SE (HSE) (April-September) and low SE (LSE) (October-March). The outcome was the development of acute ischemic events (acute coronary syndrome, stroke, or transient ischemic attack), heart failure, or death. Mean follow-up was 2.15 ± 0.99 years. Calcidiol and P levels were higher in HSE group. In the whole population, calcidiol (HR = 0.84 for each 5 ng/ml increase, 95% CI = 0.71-0.99; p = 0.038) and FGF-23 (HR = 1.14 for each 100 RU/ml increase, 95% CI = 1.05-1.23; p = 0.009) were predictors of the outcome, along with age, hypertension, body-mass index, peripheral artery disease, and P levels. In the LSE subgroup, calcidiol (HR = 0.75; 95% CI = 0.57-0.99; p = 0.034) and FGF-23 (HR = 1.34; 95% CI = 1.13-1.58; p = 0.003) remained as predictors of the outcome. In the HSE group calcidiol and FGF-23 had not independent prognostic value. CONCLUSIONS: In patients with stable CAD, low calcidiol and high FGF-23 plasma levels predict an adverse prognosis only when the sample is obtained during the months with LSE. SE should be taken into account in the clinical practice.

Diagnostic approaches for diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a cardiac dysfunction which affects approximately 12% of diabetic patients, leading to overt heart failure and death. However, there is not an efficient and specific methodology for DCM diagnosis, possibly because molecular mechanisms are not fully elucidated, and it remains asymptomatic for many years. Also, DCM frequently coexists with other comorbidities such as hypertension, obesity, dyslipidemia, and vasculopathies. Thus, human DCM is not specifically identified after heart failure is established. In this sense, echocardiography has been traditionally considered the gold standard imaging test to evaluate the presence of cardiac dysfunction, although other techniques may cover earlier DCM detection by quantification of altered myocardial metabolism and strain. In this sense, Phase-Magnetic Resonance Imaging and 2D/3D-Speckle Tracking Echocardiography may potentially diagnose and stratify diabetic patients. Additionally, this information could be completed with a quantification of specific plasma biomarkers related to related to initial stages of the disease. Cardiotrophin-1, activin A, insulin-like growth factor binding protein-7 (IGFBP-7) and Heart fatty-acid binding protein have demonstrated a stable positive correlation with cardiac hypertrophy, contractibility and steatosis responses. Thus, we suggest a combination of minimally-invasive diagnosis tools for human DCM recognition based on imaging techniques and measurements of related plasma biomarkers.

Parathormone Levels Are Independently Associated with the Presence of Left Ventricular Hypertrophy in Patients with Coronary Artery Disease.

BACKGROUND: Abnormalities of mineral metabolism and inflammation may affect the cardiovascular system. We have assessed the relationship of left ventricular hypertrophy (LVH) with inflammation and mineral metabolism. METHODS: LVH was measured in 146 outpatients with stable coronary artery disease (SCAD) using echocardiography. Calcidiol (a vitamin D metabolite), parathyroid hormone (PTH), fibroblast growth factor-23, high-sensitivity C-reactive protein, MCP-1 (monocyte chemoattractant protein-1), galectin-3, NGAL (neutrophil gelatinase-associated lipocalin), and sTWEAK (soluble TNF-related weak inducer of apoptosis) plasma levels were studied. RESULTS: LVH, defined as septal thickness ≥11 mm, was present in 19.9% of cases. These patients were older [75.0 (61.0-81.0) vs 64.0 (51.0-76.0) years; p=0.002], had higher prevalence of left ventricular ejection fraction (LVEF)>40%, and had higher PTH [84.7 (59.6-104.7) vs 63.2 (49.2-85.2) pg/ml; p=0.007], galectin-3 [9.6 (8.0-11.1) vs 8.3 (6.9-9.9) ng/ml; p=0.037], and NGAL (208.5±87.6 vs 173.9±73.4 ng/ml; p=0.031) plasma levels than those without LVH. Glomerular filtration rate was lower in patients with LVH than in those without it (65.1±20.0 vs 74.7±19.9 mL/min/1.73 m2; p=0.021). There were no significant differences in hypertension (79.3 vs 68.4%; p=0.363) or sex between both groups. Variables showing differences based on univariate analysis and hypertension were entered into a logistic regression analysis. Only age [odds ratio (OR) =1.052 (1.011-1.096); p=0.013], PTH plasma levels [OR=1.017 (1.003-1.031); p=0.021], and LVEF>40% [OR=7.595 (1.463-39.429); p=0.016] were independent predictors of LVH. CONCLUSIONS: In patients with SCAD, elevated PTH levels are independently associated with the presence of LVH. Further studies are needed to elucidate the role of PTH in the development of myocardial hypertrophy.

Updating experimental models of diabetic cardiomyopathy.

Diabetic cardiomyopathy entails a serious cardiac dysfunction induced by alterations in structure and contractility of the myocardium. This pathology is initiated by changes in energy substrates and occurs in the absence of atherothrombosis, hypertension, or other cardiomyopathies. Inflammation, hypertrophy, fibrosis, steatosis, and apoptosis in the myocardium have been studied in numerous diabetic experimental models in animals, mostly rodents. Type I and type II diabetes were induced by genetic manipulation, pancreatic toxins, and fat and sweet diets, and animals recapitulate the main features of human diabetes and related cardiomyopathy. In this review we update and discuss the main experimental models of diabetic cardiomyopathy, analysing the associated metabolic, structural, and functional abnormalities, and including current tools for detection of these responses. Also, novel experimental models based on genetic modifications of specific related genes have been discussed. The study of specific pathways or factors responsible for cardiac failures may be useful to design new pharmacological strategies for diabetic patients.

Activation of toll-like receptors and inflammasome complexes in the diabetic cardiomyopathy-associated inflammation.

Diabetic cardiomyopathy is defined as a ventricular dysfunction initiated by alterations in cardiac energy substrates in the absence of coronary artery disease and hypertension. Hyperglycemia, hyperlipidemia, and insulin resistance are major inducers of the chronic low-grade inflammatory state that characterizes the diabetic heart. Cardiac Toll-like receptors and inflammasome complexes may be key inducers for inflammation probably through NF-κB activation and ROS overproduction. However, metabolic dysregulated factors such as peroxisome proliferator-activated receptors and sirtuins may serve as therapeutic targets to control this response by mitigating both Toll-like receptors and inflammasome signaling.

Alteration of energy substrates and ROS production in diabetic cardiomyopathy.

Diabetic cardiomyopathy is initiated by alterations in energy substrates. Despite excess of plasma glucose and lipids, the diabetic heart almost exclusively depends on fatty acid degradation. Glycolytic enzymes and transporters are impaired by fatty acid metabolism, leading to accumulation of glucose derivatives. However, fatty acid oxidation yields lower ATP production per mole of oxygen than glucose, causing mitochondrial uncoupling and decreased energy efficiency. In addition, the oxidation of fatty acids can saturate and cause their deposition in the cytosol, where they deviate to induce toxic metabolites or gene expression by nuclear-receptor interaction. Hyperglycemia, the fatty acid oxidation pathway, and the cytosolic storage of fatty acid and glucose/fatty acid derivatives are major inducers of reactive oxygen species. However, the presence of these species can be essential for physiological responses in the diabetic myocardium.

Proteome changes in the myocardium of experimental chronic diabetes and hypertension: role of PPARα in the associated hypertrophy.

Diabetes with or without the presence of hypertension damages the heart. However, there is currently a lack of information about these associated pathologies and the alteration of linked proteins. For these reasons, we were interested in the potential synergistic interaction of diabetes and hypertension in the heart, focusing on the proteome characterization of the pathological phenotypes and the associated hypertrophic response. We treated normotensive and spontaneously hypertensive (SHR) rats with either streptozotocin or vehicle. After 22weeks, type-I diabetic (DM1), SHR, SHR/DM1 and control left-ventricles were studied using proteomic approaches. Proteomics revealed that long-term DM1, SHR and SHR/DM1 rats exhibited 24, 53 and 53 altered proteins in the myocardia, respectively. DM1 myocardium showed over-expression of apoptotic and cytoskeleton proteins, and down-regulation of anti-apoptotic and mitochondrial metabolic enzymes. In both SHR and SHR/DM1 these changes were exacerbated and free fatty-acid (FFA) ß-oxidation enzymes were additionally decreased. Furthermore, SHR/DM1 hearts exhibited a misbalance of specific pro-hypertrophic, anti-apoptotic and mitochondrial ATP-carrier factors, which could cause additional damage. Differential proteins were validated and then clustered into different biological pathways using bioinformatics. These studies suggested the implication of FFA-nuclear receptors and hypertrophic factors in these pathologies. Although key ß-oxidation enzymes were not stimulated in DM1 and hypertensive hearts, peroxisome proliferator-activated receptors-α (PPARα) were potentially activated for other responses. In this regard, PPARα stimulation reduced hypertrophy and pro-hypertrophic factors such as annexin-V in high-glucose and angiotensin-II induced cardiomyocytes. Thus, activation of PPARα could reflect a compensatory response to the metabolic-shifted, apoptotic and hypertrophic status of the hypertensive-diabetic cardiomyopathy.

Potential role of nuclear factor κB in diabetic cardiomyopathy.

Diabetic cardiomyopathy entails the cardiac injury induced by diabetes independently of any vascular disease or hypertension. Some transcription factors have been proposed to control the gene program involved in the setting and development of related processes. Nuclear factor-kappa B is a pleiotropic transcription factor associated to the regulation of many heart diseases. However, the nuclear factor-kappa B role in diabetic cardiomyopathy is under investigation. In this paper, we review the nuclear factor-kappa B pathway and its role in several processes that have been linked to diabetic cardiomyopathy, such as oxidative stress, inflammation, endothelial dysfunction, fibrosis, hypertrophy and apoptosis.

Myocardial fibrosis and apoptosis, but not inflammation, are present in long-term experimental diabetes.

The aim of this paper is to study the myocardial damage secondary to long-term streptozotocin-induced type 1 diabetes mellitus (DM1). Normotensive and spontaneously hypertensive rats (SHR) received either streptozotocin injections or vehicle. After 22 or 6 wk, DM1, SHR, DM1/SHR, and control rats were killed, and the left ventricles studied by histology, quantitative PCR, Western blot, ELISA, and electromobility shift assay. Cardiomyocyte cultures were also performed. The expression of profibrotic factors, transforming growth factor-beta (TGF-beta1), connective tissue growth factor, and matrix proteins was increased, and the TGF-beta1-linked transcription factors phospho-Smad3/4 and activator protein-1 were activated in the DM1 myocardium. Proapoptotic molecules FasL, Fas, Bax, and cleaved caspase-3 were also augmented. Myocardial injury in long-term hypertension shared these features. In addition, hypertension was associated with activation of NF-kappaB, increased inflammatory cell infiltrate, and expression of the mediators [interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, monocyte chemoattractant protein 1, vascular cell adhesion molecule 1, angiotensinogen, and oxidants], which were absent in long-term DM1. At this stage, the combination of DM1 and hypertension resulted in nonsignificant additive effects. Moreover, the coexistence of DM1 blunted the inflammatory response to hypertension. Anti-inflammatory IL-10 and antioxidants were induced in long-term DM1 and DM1/SHR hearts. Myocardial inflammation was, however, observed in the short-term model. In cultured cardiomyocytes, IL-10, TGF-beta1, and catalase blocked the glucose-stimulated expression of proinflammatory genes. Fibrosis and apoptosis are features of long-term myocardial damage in experimental DM1. Associated hypertension does not induce additional changes. Myocardial inflammation is present in hypertension and short-term DM1, but is not a key feature in long-term DM1. Local reduction of proinflammatory factors and expression of anti-inflammatory and antioxidant molecules may underlie this effect.

Plasma fingerprinting with GC-MS in acute coronary syndrome.

New biomarkers of cardiovascular disease are needed to augment the information obtained from traditional indicators and to illuminate disease mechanisms. One of the approaches used in metabolomics/metabonomics for that purpose is metabolic fingerprinting aiming to profile large numbers of chemically diverse metabolites in an essentially nonselective way. In this study, gas chromatography-mass spectrometry was employed to evaluate the major metabolic changes in low molecular weight plasma metabolites of patients with acute coronary syndrome (n = 9) and with stable atherosclerosis (n = 10) vs healthy subjects without significant differences in age and sex (n = 10). Reproducible differences between cases and controls were obtained with pattern recognition techniques, and metabolites accounting for higher weight in the classification have been identified through their mass spectra. On this basis, it seems inherently plausible that even a simple metabolite profile might be able to offer improved clinical diagnosis and prognosis, but in addition, specific markers are being identified.

El tratamiento con dosis altas de atorvastatina disminuye la inflamación en la aterosclerosis carotídea humana / High-dose atorvastatin therapy reduces inflammation in human carotid atherosclerosis

Introducción. Las estatinas mejoran la estabilidad de la placa al disminuir la actividad inflamatoria. Hemos analizado el efecto de un ciclo corto de tratamiento con altas dosis de atorvastatina sobre la inflamación de la placa de ateroma carotídea humana. Materiales y métodos. Veinte pacientes programados para endarterectomía carotídea electiva, y sin tratamiento previo con estatinas, fueron asignados aleatoriamente en el momento de la indicación quirúrgica para recibir atorvastatina 80 mg/día (n = 11) o no estatinas (n = 9) hasta el día de la cirugía (1 mes). En las placas extraídas durante la endarterectomía se analizaban el infiltrado de macrófagos, y la expresión de MCP-1 (monocyte chemoattractant protein-1) y ciclooxigenasa-2 (COX-2) por inmunohistoquímica. La activación de NF-kB se estudió con la técnica de Southwestern. Resultados. La atorvastatina disminuyó las concentraciones de colesterol total (118 ± 10 frente a 191 ± 10 mg/dl; p = 0,016) y de lipoproteínas de baja densidad (LDL) (63 ± 9 frente a 125 ± 9 mg/dl; p = 0,038), mientras que no hubo cambios en el grupo control. Los triglicéridos y las lipoproteínas de alta densidad (HDL) no variaron significativamente en ningún grupo. Las placas ateroscleróticas del grupo de atorvastatina presentaron una reducción significativa del infiltrado de macrófagos (2,5 ± 1% frente a 9,3 ± 2,4%; p < 0,05), y de la expresión de MCP-1 (11 ± 1% frente a 24 ± 4%; p < 0,05) y COX-2 (16 ± 2,3% frente a 34 ± 4,4%; p < 0,05). El número de núcleos con actividad de NF-kB era menor en las placas de los pacientes que recibieron atorvastatina que en los que no recibieron tratamiento (5.706 ± 1.260 frente a 8.063 ± 1.308; p < 0,05). Conclusiones. El tratamiento intensivo con atorvastatina disminuye la inflamación en las placas de aterosclerosis carotídea humana en sólo 1 mes (AU)

Introduction. Statins improve plaque stability by diminishing inflammatory activity. We analyzed the effect of short-term high-dose atorvastatin on plaque inflammation in human carotid atherosclerosis. Materials and methods. Twenty patients scheduled to undergo elective carotid endarterectomy without previous statin treatment were randomized at the time of surgical indication to receive either atorvastatin 80 mg/day (n = 11) or no statins (n = 9) until surgery (1 month later). Atherosclerotic plaques were analyzed by immunohistochemistry to investigate macrophage infiltrate, and expression of monocyte chemoattractant protein-1 (MCP-1) and cyclooxygenase-2 (COX-2). In addition, nuclear factor-kB (NF-kB) activity was studied by Southwestern histochemistry. Results. Atorvastatin decreased serum levels of total cholesterol (118 ± 10 versus 191 ± 10 mg/dl; p = 0.016) and low-density lipoprotein (63 ± 9 versus 125 ± 9 mg/dl; p = 0.038), while no changes were noted in the control group. Triglycerides and high-density lipoprotein showed no significant changes in either of the two groups. Carotid atherosclerotic plaques from the atorvastatin group demonstrated a significant reduction in macrophage infiltration (2.5 ± 1% versus 9.3 ± 2.4%; p < 0.05) and expression of MCP-1 (11 ± 1% versus 24 ± 4%; p < 0.05) and COX-2 (16 ± 2.3% versus 34 ± 4.4%; p < 0.05). The number of nuclei active for NF-kB was lower in plaques from patients that received atorvastatin than in those from the non-treated group (5,706 ± 1,260 versus 8063 ± 1,308; p < 0.05). Conclusions. Intensive atorvastatin therapy decreases inflammatory activity in human carotid atherosclerotic plaques in as little as 1 month (AU)

Fibrohistiocitoma maligno primario de mama. Implicaciones diagnósticas y terapéuticas / Primitive breast malignant fibrous histiocytoma. Diagnostics and treatment implications

Los sarcomas primarios de la mama representan menos del 1 por ciento de todos los cánceres mamarios. El Histiocitoma fibroso maligno forma parte de las variedades histológicas más infrecuentes de este grupo de tumores que clínicamente se presentan como una masa sólida, indolora, bien delimitada, móvil y con características radiológicas de benignidad. Su diagnóstico inicial está comprometido ante la necesidad de un estudio histológico que permita un diagnóstico diferencial con otras patologías mesenquimales. La biopsia diferida nos definirá, por tanto, sus caracteres anatomopatológicos, su nivel de agresividad y poder metastásico y establecerá el diagnóstico definitivo y certero, fundamental para intuir la evolución de la enfermedad y poder establecer una hipótesis pronóstica. Tradicionalmente la mastectomía simple ha sido el tratamiento elegido, aunque en la actualidad, las series de estudios multicéntricos están encaminados a demostrar iguales tasas de supervivencia con la escisión local amplia del tumor. Existe aún gran controversia en cuanto a la necesidad de un tratamiento adyuvante con radioterapia o con quimioterapia, siendo necesarios estudios prospectivos bien diseñados para establecer unos protocolos de consenso (AU)

Regulation of matrix proteins and impact on vascular structure.

The vascular extracellular matrix is responsible for the mechanical properties of the vessel wall and is also involved in biologic processes such as cellular adhesion, regulation, and proliferation. Thus, an adequate balance of its components is necessary for the normal functioning of the vasculature. Vascular disorders affect this balance, and this plays a key role in their pathophysiology. Atherogenesis is accompanied by an increase in matrix deposition in response to low-density lipoprotein accumulation. However, this matrix, mainly collagen, also has a protective role by forming a fibrous cap around the lipid core, avoiding contact with blood. A decrease in the amount of collagen will weaken the cap and make it prone to rupture, leading to thrombosis and acute coronary syndromes. In hypertension, the increase in matrix deposition results in vascular stiffness and cardiac dysfunction. In this paper, we discuss the relevance of matrix regulation in these conditions.

Atorvastatin reduces NF-kappaB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells.

Cardiovascular mortality, mainly due to the rupture of unstable atherosclerotic plaques, is reduced by 3-hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors. Inflammatory cells, attracted to the vascular lesion by chemokines, have been implicated in the process of the plaque rupture. In cultured vascular smooth muscle cells (VSMC) and U937 mononuclear cells we have studied the effect of Atorvastatin (Atv) on nuclear factor kappaB (NF-kappaB) activity, an inducer of the mRNA expression of chemokines such as interferon-inducible protein 10 (IP-10) and monocyte chemoattractant protein 1 (MCP-1). Angiotensin II (Ang II) and tumor necrosis factor alpha (TNF-alpha) increased NF-kappaB activity in VSMC (2 and 5-fold, respectively). Preincubation of cells with 10(-7) mol/l Atv diminished this activation (44 and 53%). The inhibition was reversed by mevalonate, farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), but not by other isoprenoids. Coinciding with the NF-kappaB activation in VSMC, there was a diminution of cytoplasmic IkappaB levels that was recovered by pretreatment with Atv. Ang II and TNF-alpha induced the expression of IP-10 (1.5 and 3.4-fold) and MCP-1 (2.4 and 4-fold) in VSMC. Atv reduced this overexpression around 38 and 35% (IP-10), and 54 and 39% (MCP-1), respectively. Our results strongly suggest that Atv, through the inhibition of NF-kappaB activity and chemokine gene expression, could reduce the inflammation within the atherosclerotic lesion and play a role in the stabilization of the lesion.