A Novel Technique of Placing Desfibrillator Leads in Patients with Persistent Left Superior Vena Cava.

Persistent left superior vena cava is the most common thoracic venous anomaly. It is usually asymptomatic, but it can make implanting intracardiac devices difficult.We present a novel technique to facilitate desfibrillator lead implantation in patients with persistent left superior vena cava and the absence of the right superior vena cava. We used a fixed-curve Selectra 3D 65-42 cm sheath (Biotronik), orienting it toward the tricuspid valve (TV) by rotating it counter-clockwise. During follow-up, the electrodes remained stable.Our technique was safe, simple, and feasible for patients with this complex venous anatomy.

Short-term dietary intervention improves endothelial dysfunction induced by high-fat feeding in mice through upregulation of the AMPK-CREB signaling pathway.

AIM: In addition to functioning as an energy sensor switch, AMPK plays a key role in the maintenance of cardiovascular homeostasis. However, obesity disrupts AMPK signaling, contributing to endothelial dysfunction and cardiovascular disease. This study aimed to elucidate if a short-term dietary intervention consisting in replacing the high-fat diet with a standard diet for 2 weeks could reverse obesity-induced endothelial dysfunction via AMPK-CREB activation. METHODS: For this, 5-week-old male C57BL6J mice were fed a standard (Chow) or a high-fat (HF) diet for 8 weeks. The HF diet was replaced by the chow diet for the last 2 weeks in half of HF mice, generating 3 groups: Chow, HF and HF-Chow. Vascular reactivity and western-blot assays were performed in the thoracic aorta. RESULTS: Returning to a chow diet significantly reduced body weight and glucose intolerance. Relaxant responses to acetylcholine and the AMPK activator (AICAR) were significantly impaired in HF mice but improved in HF-Chow mice. The protein levels of AMPKα, p-CREB and antioxidant systems (heme oxygenase-1 (HO-1) and catalase) were significantly reduced in HF but normalized in HF-Chow mice. CONCLUSION: Improving dietary intake by replacing a HF diet with a standard diet improves AMPK-mediated responses due to the upregulation of the AMPK/CREB/HO-1 signaling pathway.

Angiotensin II type 2 receptor as a novel activator of brown adipose tissue in obesity.

The angiotensin II type 2 receptor (AT2R) exerts vasorelaxant, anti-inflammatory, and antioxidant properties. In obesity, its activation counterbalances the adverse cardiovascular effects of angiotensin II mediated by the AT1R. Preliminary results indicate that it also promotes brown adipocyte differentiation in vitro. Our hypothesis is that AT2R activation could increase BAT mass and activity in obesity. Five-week-old male C57BL/6J mice were fed a standard or a high-fat (HF) diet for 6 weeks. Half of the animals were treated with compound 21 (C21), a selective AT2R agonist, (1 mg/kg/day) in the drinking water. Electron transport chain (ETC), oxidative phosphorylation, and UCP1 proteins were measured in the interscapular BAT (iBAT) and thoracic perivascular adipose tissue (tPVAT) as well as inflammatory and oxidative parameters. Differentiation and oxygen consumption rate (OCR) in the presence of C21 was tested in brown preadipocytes. In vitro, C21-differentiated brown adipocytes showed an AT2R-dependent increase of differentiation markers (Ucp1, Cidea, Pparg) and increased basal and H+ leak-linked OCR. In vivo, HF-C21 mice showed increased iBAT mass compared to HF animals. Both their iBAT and tPVAT showed higher protein levels of the ETC protein complexes and UCP1, together with a reduction of inflammatory and oxidative markers. The activation of the AT2R increases BAT mass, mitochondrial activity, and reduces markers of tissue inflammation and oxidative stress in obesity. Therefore, insulin reduction and better vascular responses are achieved. Thus, the activation of the protective arm of the renin-angiotensin system arises as a promising tool in the treatment of obesity.

AT2R stimulation with C21 prevents arterial stiffening and endothelial dysfunction in the abdominal aorta from mice fed a high-fat diet.

The aim of the present study was to evaluate the effect of Compound 21 (C21), a selective AT2R agonist, on the prevention of endothelial dysfunction, extracellular matrix (ECM) remodeling and arterial stiffness associated with diet-induced obesity (DIO). Five-week-old male C57BL/6J mice were fed a standard (Chow) or high-fat diet (HF) for 6 weeks. Half of the animals of each group were simultaneously treated with C21 (1 mg/kg/day, in the drinking water), generating four groups: Chow C, Chow C21, HF C, and HF C21. Vascular function and mechanical properties were determined in the abdominal aorta. To evaluate ECM remodeling, collagen deposition and TGF-ß1 concentrations were determined in the abdominal aorta and the activity of metalloproteinases (MMP) 2 and 9 was analyzed in the plasma. Abdominal aortas from HF C mice showed endothelial dysfunction as well as enhanced contractile but reduced relaxant responses to Ang II. This effect was abrogated with C21 treatment by preserving NO availability. A left-shift in the tension-stretch relationship, paralleled by an augmented ß-index (marker of intrinsic arterial stiffness), and enhanced collagen deposition and MMP-2/-9 activities were also detected in HF mice. However, when treated with C21, HF mice exhibited lower TGF-ß1 levels in abdominal aortas together with reduced MMP activities and collagen deposition compared with HF C mice. In conclusion, these data demonstrate that AT2R stimulation by C21 in obesity preserves NO availability and prevents unhealthy vascular remodeling, thus protecting the abdominal aorta in HF mice against the development of endothelial dysfunction, ECM remodeling and arterial stiffness.

Antiphospholipid Antibodies From Women With Pregnancy Morbidity and Vascular Thrombosis Induce Endothelial Mitochondrial Dysfunction, mTOR Activation, and Autophagy.

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by thrombosis and pregnancy morbidity (PM) obstetric events together with persistent high titers of circulating antiphospholipid antibodies (aPL). Several mechanisms that explain the development of thrombosis and PM in APS include the association of aPL with alterations in the coagulation cascade and inflammatory events. Other mechanisms disturbing cellular homeostases, such as mitochondrial dysfunction, autophagy, and cell proliferation, have been described in other autoimmune diseases. Therefore, the objective of this study was to investigate the impact of aPL from different patient populations on endothelial cell mitochondrial function, activation of the mammalian target of rapamycin (mTOR) and autophagy pathways, and cellular growth. Using an in vitro model, human umbilical vein endothelial cells (HUVECs) were treated with polyclonal immunoglobulin G (IgG) purified from the serum of women with both PM and vascular thrombosis (PM/VT), with VT only (VT), or with PM and non-criteria aPL (seronegative-obstetric APS, SN-OAPS). We included IgG from women with PM without aPL (PM/aPL-) and healthy women with previous uncomplicated pregnancies (normal human serum, NHS) as control groups. Mitochondrial function, mTOR activation, autophagy, and cell proliferation were evaluated by Western blotting, flow cytometry, and functional assays. IgG from women with PM/VT increased HUVEC mitochondrial hyperpolarization and activation of the mTOR and autophagic pathways, while IgG from patients with VT induced endothelial autophagy and cell proliferation in the absence of elevated mTOR activity or mitochondrial dysfunction. IgG from the SN-OAPS patient group had no effect on any of these HUVEC responses. In conclusion, aPL from women with PM and vascular events induce cellular stress evidenced by mitochondrial hyperpolarization and increased activation of the mTOR and autophagic pathways which may play a role in the pathogenesis of obstetric APS.

Prevention of Teratogenesis in Pregnancies of Obese Rats by Vitamin E Supplementation.

Congenital malformations are a common adverse outcome in pregnancies complicated by pregestational obesity, although the underlying mechanisms are still unrevealed. Our aim was to study the effect of oxidative stress in obesity-induced teratogenesis. Wistar rats were fed a high-fat diet for 13 weeks, with (OE group) or without (O group) vitamin E supplementation. Then, rats were mated and sacrificed at day 11.5 of gestation. Embryos from O dams presented a 25.9 ± 3.5% rate of malformations (vs. 8.7 ± 3.4% in C rats), which was reduced in the OE group (11.5 ± 2.3%). Pregestational obesity induced hepatic protein and DNA oxidation and a decline in antioxidant enzymes. Importantly, glutathione content was also decreased, limiting the availability of this antioxidant in the embryos. Vitamin E supplementation efficiently maintained glutathione levels in the obese mothers, which could be used in their embryos to prevent oxidation-induced malformations. To test the effect of decreasing glutathione levels alone in a cell culture model of neuroepithelium, murine embryonic stem cells (ESC) were induced to form neuronal precursors and glutathione synthesis was inhibited with the gamma-glutamylcysteine synthesis inhibitor, buthionine sulfoximine (BSO). BSO inhibited the expression of Pax3, a gene required for neural tube closure that is also inhibited by oxidative stress. Taken together, our data indicate that obesity causes malformations through the depletion of maternal glutathione, thereby decreasing glutathione-dependent free radical scavenging in embryos, which can be prevented by vitamin E supplementation.

C21 preserves endothelial function in the thoracic aorta from DIO mice: role for AT2, Mas and B2 receptors.

Compound 21 (C21), a selective agonist of angiotensin II type 2 receptor (AT2R), induces vasodilation through NO release. Since AT2R seems to be overexpressed in obesity, we hypothesize that C21 prevents the development of obesity-related vascular alterations. The main goal of the present study was to assess the effect of C21 on thoracic aorta endothelial function in a model of diet-induced obesity (DIO) and to elucidate the potential cross-talk among AT2R, Mas receptor (MasR) and/or bradykinin type 2 receptor (B2R) in this response. Five-week-old male C57BL6J mice were fed a standard (CHOW) or a high-fat diet (HF) for 6 weeks and treated daily with C21 (1 mg/kg p.o) or vehicle, generating four groups: CHOW-C, CHOW-C21, HF-C, HF-C21. Vascular reactivity experiments were performed in thoracic aorta rings. Human endothelial cells (HECs; EA.hy926) were used to elucidate the signaling pathways, both at receptor and intracellular levels. Arteries from HF mice exhibited increased contractions to Ang II than CHOW mice, effect that was prevented by C21. PD123177, A779 and HOE-140 (AT2R, Mas and B2R antagonists) significantly enhanced Ang II-induced contractions in CHOW but not in HF-C rings, suggesting a lack of functionality of those receptors in obesity. C21 prevented those alterations and favored the formation of AT2R/MasR and MasR/B2R heterodimers. HF mice also exhibited impaired relaxations to acetylcholine (ACh) due to a reduced NO availability. C21 preserved NO release through PKA/p-eNOS and AKT/p-eNOS signaling pathways. In conclusion, C21 favors the interaction among AT2R, MasR and B2R and prevents the development of obesity-induced endothelial dysfunction by stimulating NO release through PKA/p-eNOS and AKT/p-eNOS signaling pathways.

High levels of maternal total tri-iodothyronine, and low levels of fetal free L-thyroxine and total tri-iodothyronine, are associated with altered deiodinase expression and activity in placenta with gestational diabetes mellitus.

Gestational Diabetes Mellitus (GDM) is characterized by abnormal maternal D-glucose metabolism and altered insulin signaling. Dysregulation of thyroid hormones (TH) tri-iodethyronine (T3) and L-thyroxine (T4) Hormones had been associated with GDM, but the physiopathological meaning of these alterations is still unclear. Maternal TH cross the placenta through TH Transporters and their Deiodinases metabolize them to regulate fetal TH levels. Currently, the metabolism of TH in placentas with GDM is unknown, and there are no other studies that evaluate the fetal TH from pregnancies with GDM. Therefore, we evaluated the levels of maternal TH during pregnancy, and fetal TH at delivery, and the expression and activity of placental deiodinases from GDM pregnancies. Pregnant women were followed through pregnancy until delivery. We collected blood samples during 10-14, 24-28, and 36-40 weeks of gestation for measure Thyroid-stimulating hormone (TSH), Free T4 (FT4), Total T4 (TT4), and Total T3 (TT3) concentrations from Normal Glucose Tolerance (NGT) and GDM mothers. Moreover, we measure fetal TSH, FT4, TT4, and TT3 in total blood cord at the delivery. Also, we measured the placental expression of Deiodinases by RT-PCR, western-blotting, and immunohistochemistry. The activity of Deiodinases was estimated quantified rT3 and T3 using T4 as a substrate. Mothers with GDM showed higher levels of TT3 during all pregnancy, and an increased in TSH during second and third trimester, while lower concentrations of neonatal TT4, FT4, and TT3; and an increased TSH level in umbilical cord blood from GDM. Placentae from GDM mothers have a higher expression and activity of Deiodinase 3, but lower Deiodinase 2, than NGT mothers. In conclusion, GDM favors high levels of TT3 during all gestation in the mother, low levels in TT4, FT4 and TT3 at the delivery in neonates, and increases deiodinase 3, but reduce deiodinase 2 expression and activity in the placenta.

Will global change modify the distribution of the Anadenanthera colubrina (Fabales: Fabaceae) plant, a key species in dry tropical forest?

Introduction: Seasonally dry tropical forests (SDTF) are one of the most threatened terrestrial ecosystems on the planet as a consequence of global change. They harbor high biodiversity and provide a wide range of ecosystem services; therefore, their conservation is a priority worldwide. Climate warming, as well as land use patterns, are leading to species distribution range shifts. Objective: The objective of this work was to study the current and future potential distribution of a SDTF representative tree species (Anadenanthera colubrina) in the Argentinian Sub Andean Piedmont nucleus and to assess the effects of land use and climate changes. Methods: Current and future potential distribution was modeled with Maxent, using 49 presence points and 20 variables. Climate change effects were estimated in four different temperature and carbon dioxide concentration scenarios. Land use changes were determined subtracting the deforested area until 2017 to the current and future potential distribution of the species. Results: A. colubrina current distribution represents 18 % of Northwestern Argentina. Land use changes decreased almost 25 % of it and climate change will probably cause a retraction in the East and a slight expansion towards the West and South of the current distribution. The synergistic effect of land use and climate change projected to the worst scenario would reduce 63 % of its current distribution. Conclusions: Our data demonstrate the central role of distribution range studies to assess the effects of anthropic activities. Climate change and land use change would have a negative and synergistic effect on the distribution of A. colubrina. Although a possible expansion of the Sub Andean Piedmont nucleus of SDTF would occur, this expansion may be limited by the Sub Andean mountain range that could act as an orographic barrier.

Introducción: Los Bosques Tropicales Estacionalmente Secos (BTES) son unos de los ecosistemas terrestres más amenazados del planeta como consecuencia del cambio global. Estos bosques albergan una alta biodiversidad y proporcionan una amplia gama de servicios ecosistémicos, por lo que su conservación es una prioridad a nivel mundial. El cambio climático y el cambio en los usos del suelo están afectando la distribución de las especies. Objetivo: El objetivo de este trabajo fue estudiar la distribución potencial de una especie representativa de BTES (Anadenanthera colubrina) en el núcleo del Piedemonte subandino argentino y evaluar los efectos del cambio en los usos del suelo y del cambio climático sobre su distribución. Métodos: La distribución actual y futura de A. colubrina fue modelada con Maxent, utilizando 49 puntos de presencia y 20 variables. Los efectos del cambio climático se estimaron en cuatro escenarios que difieren en los niveles de temperatura y concentración de dióxido de carbono. Los efectos del cambio en el uso del suelo se estimaron descontando el área deforestada hasta el 2017 a la distribución actual y futura de la especie. Resultados: La distribución actual de A. colubrina representa un 18 % del Noroeste Argentino. Los cambios en el uso del suelo produjeron una disminución del 25 % del área de distribución actual y el cambio climático probablemente causará una retracción al Este y una expansión hacia el oeste y sur de su distribución. El efecto sinérgico del cambio en el uso del suelo y el cambio climático podría producir una pérdida del 63 % considerando el peor escenario de cambio climático. Conclusiones: Nuestros datos demuestran el rol fundamental de los estudios de distribución para evaluar los efectos de las actividades antrópicas. Los cambios en los usos del suelo y el cambio climático podrían tener un efecto negativo y sinérgico sobre la distribución de A. colubrina. La posible expansión del núcleo Piedemonte de SDTF hacia el oeste y el sur de la región no estaría limitada por cambios en el uso del suelo, aunque las cadenas montañosas podrían actuar como barreras orográficas y limitar la expansión.

Patient and system delays in the treatment of acute coronary syndrome.

INTRODUCTION: Early reperfusion for patients with ST-segment elevation myocardial infarction (STEMI) is indicated by the European Society of Cardiology, while a timely invasive strategy is recommended for patients with high-risk and intermediate-risk non-ST-elevation acute coronary syndromes (NSTE-ACS). This study aims to assess patient and system delays according to diagnosis and risk profile, and to identify predictors of prolonged delay. METHODS: We assembled a cohort of patients (n=939) consecutively admitted to the cardiology department of two hospitals, one in the metropolitan area of Porto and one in the north-east region of Portugal, between August 2013 and December 2014. RESULTS: The proportion of patients with time from symptom onset to first medical contact (FMC) ≥120 min was highest among high-risk NSTE-ACS (57.7%), followed by intermediate-risk NSTE-ACS (52.1%) and STEMI (43.3%). Regardless of diagnosis and risk stratification, use of own transportation and inability to interpret cardiac symptoms correctly were associated with prolonged delays. Regarding system delays, we found that 78.0% of patients with STEMI and 65.8% of patients with high-risk NSTE-ACS were treated in a timeframe exceeding the recommended limits. Admission to a non-percutaneous coronary intervention-capable hospital, admission on weekends and complications at admission were associated with prolonged delays to treatment. CONCLUSIONS: Due to both patient and system delays, a large proportion of STEMI and high-risk NSTE-ACS patients still fail to have access to timely reperfusion.

Impact of caloric restriction on AMPK and endoplasmic reticulum stress in peripheral tissues and circulating peripheral blood mononuclear cells from Zucker rats.

The activation of endoplasmic reticulum (ER) stress and a reduction of AMP-dependent protein kinase (AMPK) phosphorylation have been described in obesity. We hypothesize that a moderate caloric restriction (CR) might contribute to reducing ER stress and increasing AMPK phosphorylation in peripheral tissues from genetically obese Zucker fa/fa rats and in peripheral blood mononuclear cells (PBMCs). Zucker Lean and Zucker fa/fa rats were fed with chow diet either ad libitum (AL) (C, as controls) or 80% of AL (CR) for 2 weeks, giving rise to four experimental groups: Lean C, Lean CR, fa/fa C and fa/fa CR. CR significantly increased AMPK phosphorylation in the liver, perirenal adipose tissue (PRAT) and PBMCs from fa/fa rats but not in the subcutaneous AT (SCAT), suggesting a reduced response of SCAT to CR. Liver samples of fa/fa rats exhibited an increased mRNA expression of PERK, EIF-2α, XBP-1(s), Chop and caspase 3, which was significantly reduced by CR. PRAT exhibited an overexpression of Edem and PDIA-4 in fa/fa rats, but only PDIA-4 expression was reduced by CR. eIF-2α phosphorylation was significantly increased in all studied tissues from fa/fa rats and reduced by CR. A negative correlation was detected between p-AMPK and p-eIF-2α in the liver, PRAT and PBMCs from fa/fa rats but not in SCAT. This study shows that a moderate CR reduces ER stress and improves AMPK phosphorylation in several peripheral tissues and in circulating PBMCs, suggesting that alterations observed in PBMCs could reflect metabolic alterations associated with obesity.

Relevance of control diet choice in metabolic studies: impact in glucose homeostasis and vascular function.

The experimental approach for the study of cardiometabolic disorders requires the use of animal models fed with commercial diets whose composition differs notably, even between diets used for control groups. While chow diets are usually made of agricultural by-products, purified low-fat diets (LF) contain a higher percentage of easy metabolizable carbohydrates, together with a reduced amount of polyunsaturated fatty acids, micronutrients and fiber, all associated with metabolic and vascular dysfunction. We hypothesize that the LF diet, commonly used in control animals, could promote adverse vascular and metabolic outcomes. To address this issue, 5-week-old male C57BL6J mice were fed with a standard (Chow) or a LF diet for 6 weeks. Changes in body weight, adiposity, biochemical parameters, systemic and aortic insulin sensitivity and endothelial function were recorded. LF diet did not modify body weight but significantly impaired systemic glucose tolerance and increased triglycerides and cholesterol levels. Endothelial function and aortic insulin sensitivity were significantly impaired in the LF group, due to a reduction of NO availability. These findings highlight the importance of selecting the proper control diet in metabolic studies. It may also suggest that some cardiometabolic alterations obtained in experimental studies using LF as a control diet may be underestimated.

Calidad del cuidado y mortalidad a 30 días de mujeres y varones con infarto agudo de miocardio / Quality of care and 30-day mortality of women and men with acute myocardial infarction

Introducción y objetivos: A pesar de una mayor conciencia de las disparidades en el tratamiento y los resultados entre mujeres y varones con infarto agudo de miocardio (IAM), no parece que en la última década se hayan atenuado estas diferencias. El objetivo del estudio es identificar diferencias por sexo en el tratamiento y la mortalidad a 30 días utilizando los indicadores de calidad de la Asociación de Cuidados Cardiovasculares Agudos de la Sociedad Europea de Cardiología para el IAM. Métodos: Se calcularon las proporciones y los errores estándar de los 20 indicadores de calidad en 771 pacientes con IAM que ingresaron en el servicio de cardiología de 2 hospitales terciarios en Portugal entre agosto de 2013 y diciembre de 2014. La asociación entre el indicador de calidad compuesto y la mortalidad a 30 días se analizó por regresión logística. Resultados: Significativamente menos mujeres que varones elegibles recibieron una reperfusión oportuna, tratamiento antiagregante plaquetario doble y estatinas de alta intensidad al alta y rehabilitación cardiaca. Las mujeres recibieron con menos frecuencia las intervenciones recomendadas (el 59,6 frente al 65,2%; p < 0,001) y también tuvieron una puntuación más alta del riesgo GRACE 2.0 ajustado por la mortalidad a 30 días (el 3,0 frente al 1,7%; p < 0,001). Se observó una asociación inversa entre el indicador de calidad compuesto y la mortalidad bruta a 30 días en ambos sexos (tercil de mayor rendimiento en comparación con el menor, OR = 0,08; IC95%, 0,01-0,64). Conclusiones: El porcentaje de mujeres que recibieron tratamiento óptimo en el IAM fue menor que el de varones y se asoció con una mayor mortalidad a los 30 días. Los indicadores de calidad basados en directrices tienen el potencial de mejorar la prestación y el pronóstico de la atención médica de los pacientes con IAM en general y también de reducir la brecha entre mujeres y varones

Introduction and objectives: Despite increased awareness of sex disparities in care and outcomes of acute myocardial infarction (AMI), there appears to have been no consistent attenuation of these differences over the last decade. We investigated differences by sex in management and 30-day mortality using the European Society of Cardiology Acute Cardiovascular Care Association quality indicators (QIs) for AMI. Methods: Proportions and standard errors of the 20 Acute Cardiovascular Care Association QIs were calculated for 771 patients with AMI who were admitted to the cardiology departments of 2 tertiary hospitals in Portugal between August 2013 and December 2014. The association between the composite QI and 30-day mortality was derived from logistic regression. Results: Significantly fewer eligible women than men received timely reperfusion, were discharged on dual antiplatelet therapy and high-intensity statins, and were referred to cardiac rehabilitation. Women were less likely to receive recommended interventions (59.6% vs 65.2%; P < .001) and also had higher mean GRACE 2.0 risk score-adjusted 30-day mortality (3.0% vs 1.7%; P < .001). An inverse association between the composite QI and crude 30-day mortality was observed for both sexes (OR, 0.08; 95%CI, 0.01-0.64 for the highest performance tertile vs the lowest). Conclusions: Performance in AMI management is worse for women than men and is associated with higher 30-day mortality, which is also worse for women. Evidence-based QIs have the potential to improve health care delivery and patient prognosis in the overall AMI population and may also bridge the disparity gap between women and men

Caloric restriction induces H2O2 formation as a trigger of AMPK-eNOS-NO pathway in obese rats: Role for CAMKII.

Caloric restriction (CR) improves endothelial function through the upregulation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS). Moreover, hydrogen peroxide (H2O2) is upregulated in yeast subjected to CR. Our aim was to assess if mild short-term CR increases vascular H2O2 formation as a link with AMPK and eNOS activation. Twelve-week old Zucker obese (fa/fa) and control Zucker lean male rats were fed a standard chow either ad libitum (AL, n=10) or with a 20% CR (CR, n=10) for two weeks. CR significantly improved relaxation to ACh in fa/fa rats because of an enhanced endogenous production of H2O2 in aortic rings (H2O2 levels fa/faAL=0.5 ±â€¯0.05 nmol/mg vs. H2O2 levels fa/faCR=0.76 ±â€¯0.07 nmol/mg protein; p<0.05). Expression of mitochondrial superoxide dismutase (Mn-SOD) and total SOD activity were increased in aorta from fa/fa animals after CR. In cultured aortic endothelial cells, serum deprivation or 2-deoxy-d-glucose induced a significant increase in: i) superoxide anion and H2O2 levels, ii) p-AMPK/AMPK and p-eNOS/eNOS expression and iii) nitric oxide levels. This effect was reduced by catalase and strongly inhibited by Ca2+/calmodulin-dependent kinase II (CamkII) silencing. In conclusion, we propose that mild short-term CR might be a trigger of mechanisms aimed at protecting the vascular wall by the increase of H2O2, which then activates AMPK and nitric oxide release, thus improving endothelium-dependent relaxation. In addition, we demonstrate that CAMKII plays a key role in mediating CR-induced AMPK activation through H2O2 increase.

Mechanisms of Impaired Brown Adipose Tissue Recruitment in Obesity.

Brown adipose tissue (BAT) dissipates energy to produce heat. Thus, it has the potential to regulate body temperature by thermogenesis. For the last decade, BAT has been in the spotlight due to its rediscovery in adult humans. This is evidenced by over a hundred clinical trials that are currently registered to target BAT as a therapeutic tool in the treatment of metabolic diseases, such as obesity or diabetes. The goal of most of these trials is to activate the BAT thermogenic program via several approaches such as adrenergic stimulation, natriuretic peptides, retinoids, capsinoids, thyroid hormones, or glucocorticoids. However, the impact of BAT activation on total body energy consumption and the potential effect on weight loss is still limited. Other studies have focused on increasing the mass of thermogenic BAT. This can be relevant in obesity, where the activity and abundance of BAT have been shown to be drastically reduced. The aim of this review is to describe pathological processes associated with obesity that may influence the correct differentiation of BAT, such as catecholamine resistance, inflammation, oxidative stress, and endoplasmic reticulum stress. This will shed light on the thermogenic potential of BAT as a therapeutic approach to target obesity-induced metabolic diseases.

Beneficial effects of murtilla extract and madecassic acid on insulin sensitivity and endothelial function in a model of diet-induced obesity.

Infusions of murtilla leaves exhibit antioxidant, analgesic, and anti-inflammatory properties. Several compounds that are structurally similar to madecassic acid (MA), a component of murtilla leaf extract (ethyl acetate extract, EAE), have been shown to inhibit protein tyrosine phosphatase 1B (PTP1P). The aim of this study was to evaluate if EAE and two compounds identified in EAE (MA and myricetin [MYR]) could have a beneficial effect on systemic and vascular insulin sensitivity and endothelial function in a model of diet-induced obesity. Experiments were performed in 5-week-old male C57BL6J mice fed with a standard (LF) or a very high-fat diet (HF) for 4 weeks and treated with EAE, MA, MYR, or the vehicle as control (C). EAE significantly inhibited PTP1B. EAE and MA, but not MYR, significantly improved systemic insulin sensitivity in HF mice and vascular relaxation to Ach in aorta segments, due to a significant increase of eNOS phosphorylation and enhanced nitric oxide availability. EAE, MA, and MYR also accounted for increased relaxant responses to insulin in HF mice, thus evidencing that the treatments significantly improved aortic insulin sensitivity. This study shows for the first time that EAE and MA could constitute interesting candidates for treating insulin resistance and endothelial dysfunction associated with obesity.

Quality of Care and 30-day Mortality of Women and Men With Acute Myocardial Infarction.

INTRODUCTION AND OBJECTIVES: Despite increased awareness of sex disparities in care and outcomes of acute myocardial infarction (AMI), there appears to have been no consistent attenuation of these differences over the last decade. We investigated differences by sex in management and 30-day mortality using the European Society of Cardiology Acute Cardiovascular Care Association quality indicators (QIs) for AMI. METHODS: Proportions and standard errors of the 20 Acute Cardiovascular Care Association QIs were calculated for 771 patients with AMI who were admitted to the cardiology departments of 2 tertiary hospitals in Portugal between August 2013 and December 2014. The association between the composite QI and 30-day mortality was derived from logistic regression. RESULTS: Significantly fewer eligible women than men received timely reperfusion, were discharged on dual antiplatelet therapy and high-intensity statins, and were referred to cardiac rehabilitation. Women were less likely to receive recommended interventions (59.6% vs 65.2%; P <.001) and also had higher mean GRACE 2.0 risk score-adjusted 30-day mortality (3.0% vs 1.7%; P <.001). An inverse association between the composite QI and crude 30-day mortality was observed for both sexes (OR, 0.08; 95%CI, 0.01-0.64 for the highest performance tertile vs the lowest). CONCLUSIONS: Performance in AMI management is worse for women than men and is associated with higher 30-day mortality, which is also worse for women. Evidence-based QIs have the potential to improve health care delivery and patient prognosis in the overall AMI population and may also bridge the disparity gap between women and men.

Pleiotrophin deletion alters glucose homeostasis, energy metabolism and brown fat thermogenic function in mice.

AIMS/HYPOTHESIS: Pleiotrophin, a developmentally regulated and highly conserved cytokine, exerts different functions including regulation of cell growth and survival. Here, we hypothesise that this cytokine can play a regulatory role in glucose and lipid homeostasis. METHODS: To test this hypothesis, we performed a longitudinal study characterising the metabolic profile (circulating variables and tissue mRNA expression) of gene-targeted Ptn-deficient female mice and their corresponding wild-type counterparts at different ages from young adulthood (3 months) to older age (15 months). Metabolic cages were used to investigate the respiratory exchange ratio and energy expenditure, at both 24°C and 30°C. Undifferentiated immortalised mouse brown adipocytes (mBAs) were treated with 0.1 µg/ml pleiotrophin until day 6 of differentiation, and markers of mBA differentiation were analysed by quantitative real-time PCR (qPCR). RESULTS: Ptn deletion was associated with a reduction in total body fat (20.2% in Ptn+/+ vs 13.9% in Ptn-/- mice) and an enhanced lipolytic response to isoprenaline in isolated adipocytes from 15-month-old mice (189% in Ptn+/+ vs 273% in Ptn-/- mice). We found that Ptn-/- mice exhibited a significantly lower QUICKI value and an altered lipid profile; plasma triacylglycerols and NEFA did not increase with age, as happens in Ptn+/+ mice. Furthermore, the contribution of cold-induced thermogenesis to energy expenditure was greater in Ptn-/- than Ptn+/+ mice (42.6% and 33.6%, respectively). Body temperature and the activity and expression of deiodinase, T3 and mitochondrial uncoupling protein-1 in the brown adipose tissue of Ptn-/- mice were higher than in wild-type controls. Finally, supplementing brown pre-adipocytes with pleiotrophin decreased the expression of the brown adipocyte markers Cidea (20% reduction), Prdm16 (21% reduction), and Pgc1-α (also known as Ppargc1a, 11% reduction). CONCLUSIONS/INTERPRETATION: Our results reveal for the first time that pleiotrophin is a key player in preserving insulin sensitivity, driving the dynamics of adipose tissue lipid turnover and plasticity, and regulating energy metabolism and thermogenesis. These findings open therapeutic avenues for the treatment of metabolic disorders by targeting pleiotrophin in the crosstalk between white and brown adipose tissue.

Antioxidants and Oxidative Stress: Focus in Obese Pregnancies.

The prevalence of obesity in women of childbearing age around the globe has dramatically increased in the last decades. Obesity is characterized by a low-state chronic inflammation, metabolism impairment and oxidative stress, among other pathological changes. Getting pregnant in this situation involves that gestation will occur in an unhealthy environment, that can potentially jeopardize both maternal and fetal health. In this review, we analyze the role of maternal obesity-induced oxidative stress as a risk factor to develop adverse outcomes during gestation, including reduced fertility, spontaneous abortion, teratogenesis, preeclampsia, and intrauterine growth restriction. Evidences of macromolecule oxidation increase in reactive oxygen species generation and antioxidant defense alterations are commonly described in maternal and fetal tissues. Thus, antioxidant supplementation become an interesting prophylactic and therapeutic tool, that yields positive results in cellular, and animal models. However, the results from most meta-analysis studying the effect of these therapies in complicated gestations in humans are not really encouraging. It is still to be analyzed whether these therapies could work if applied to cohorts of patients at a high risk, such as those with low concentration of antioxidants or obese pregnant women.

Sex differences in presenting symptoms of acute coronary syndrome: the EPIHeart cohort study.

OBJECTIVES: Prompt diagnosis of acute coronary syndrome (ACS) remains a challenge, with presenting symptoms affecting the diagnosis algorithm and, consequently, management and outcomes. This study aimed to identify sex differences in presenting symptoms of ACS. DESIGN: Data were collected within a prospective cohort study (EPIHeart). SETTING: Patients with confirmed diagnosis of type 1 (primary spontaneous) ACS who were consecutively admitted to the Cardiology Department of two tertiary hospitals in Portugal between August 2013 and December 2014. PARTICIPANTS: Presenting symptoms of 873 patients (227 women) were obtained through a face-to-face interview. OUTCOME MEASURES: Typical pain was defined according to the definition of cardiology societies. Clusters of symptoms other than pain were identified by latent class analysis. Logistic regression was used to quantify differences in presentation of ACS symptoms by sex. RESULTS: Chest pain was reported by 82% of patients, with no differences in frequency or location between sexes. Women were more likely to feel pain with an intensity higher than 8/10 and this association was stronger for patients aged under 65 years (interaction P=0.028). Referred pain was also more likely in women, particularly pain referred to typical and atypical locations simultaneously. The multiple symptoms cluster, which was characterised by a high probability of presenting with all symptoms, was almost fourfold more prevalent in women (3.92, 95% CI 2.21 to 6.98). Presentation with this cluster was associated with a higher 30-day mortality rate adjusted for the GRACE V.2.0 risk score (4.9% vs 0.9% for the two other clusters, P<0.001). CONCLUSIONS: While there are no significant differences in the frequency or location of pain between sexes, women are more likely to feel pain of higher intensity and to present with referred pain and symptoms other than pain. Knowledge of these ACS presentation profiles is important for health policy decisions and clinical practice.