Ventajas e inconvenientes de los nuevos anticoagulantes orales

Los fármacos antagonistas de la vitamina K (AVK) han supuesto durante años la principal estrategia farmacológica de la anticoagulación oral para la prevención y tratamiento de laenfermedad tromboembólica venosa. Sin embargo, dicho tratamiento cuenta con limitaciones que interfieren en el desarrollo de las actividades diarias, especialmente, del paciente joven, y que afectan por consiguiente a su calidad de vida, tales como la necesidad de monitorización, riesgo de hemorragia e interacciones con alimentos ricos en vitamina K y otros fármacos de frecuente uso. Estas limitaciones se han visto en gran medida solventadas con la irrupción de los nuevos anticoagulantes orales (NACOs) que, en líneas generales, han demostrado no inferioridad en cuanto a eficacia y mayor seguridad que los AVK. Este hecho ha traído consigo incertidumbre al profesional sanitario, que encuentra en las dificultades del tratamiento con NACOs (especialmente la aún escasa existencia de estudios a largo plazo fuera de ensayo clínico y el precario conocimiento acerca de la reversión de su efecto anticoagulante) un importante reto a afrontar para que sus comentadas ventajas se vean traducidas en la mejora de la calidad de vida del paciente. La superación de estas barreras clínicas, junto a otras de índole económico y administrativo, abrirían la puerta a un nuevo paradigma de la anticoagulación oral

Arterial stiffness is associated with adipokine dysregulation in non-hypertensive obese mice

This is the peer reviewed version of the following article: Vascular Pharmacology 77 (2016): 38-47, which has been published in final form at http://dx.doi.org/10.1016/j.vph.2015.05.012The aim of this study was to characterize alterations in vascular structure and mechanics in murine mesenteric arteries from obese non-hypertensive mice, as well as their relationship with adipokines. Four-week old C57BL/6J male mice were assigned either to a control (C, 10% kcal from fat) or a high-fat diet (HFD, 45% kcal from fat) for 32 weeks. HFD animals weighed 30% more than controls (p < 0.001), exhibited similar blood pressure, increased leptin, insulin and superoxide anion (O2radical dot−) levels, and reduced adiponectin levels and nitric oxide (NO) bioavailability. Arterial structure showed an outward remodeling with an increase in total number of both adventitial and smooth muscle cells in HFD. Moreover, HFD mice exhibited an increased arterial stiffness assessed by β-values (C = 2.4 ± 0.5 vs HFD = 5.3 ± 0.8; p < 0.05) and aortic pulse wave velocity (PWV, C = 3.4 ± 0.1 vs HFD = 3.9 ± 0.1; p < 0.05). β-Values and PWV positively correlated with leptin, insulin or O2radical dot− levels, whereas they negatively correlated with adiponectin levels and NO bioavailability (p < 0.01). A reduction in fenestrae number together with an increase in type-I collagen amount (p < 0.05) were observed in HFD. These data demonstrate that HFD accounts for the development of vascular remodeling and arterial stiffness associated with adipokine dysregulation and oxidative stress, independently of hypertension developmentThis work was supported by grants from Ministerio de Ciencia e Investigación (BFU2011-25303), Ministerio de Economía y Competitividad (SAF2009-09714, SAF2011-25303, BFU2012-35353), Grupos Universidad Complutense de Madrid (UCM; GR-921641), Fundación Universitaria CEU-San Pablo, Fundación Mutua Madrileña and Sociedad para el Estudio de la Salud Cardiometabólica (SESCAMET). MGO is recipient of a Ministerio de Educación y Ciencia fellowshi

Mild and short-term caloric restriction prevents obesity-induced cardiomyopathy in young zucker rats without changing in metabolites and fatty acids cardiac profile

Caloric restriction (CR) ameliorates cardiac dysfunction associated with obesity. However, most of the studies have been performed under severe CR (30-65% caloric intake decrease) for several months or even years in aged animals. Here, we investigated whether mild (20% food intake reduction) and short-term (2-weeks) CR prevented the obese cardiomyopathy phenotype and improved the metabolic profile of young (14 weeks of age) genetically obese Zucker fa/fa rats. Heart weight (HW) and HW/tibia length ratio was significantly lower in fa/fa rats after 2 weeks of CR than in counterparts fed ad libitum. Invasive pressure measurements showed that systolic blood pressure, maximal rate of positive left ventricle (LV) pressure, LV systolic pressure and LV end-diastolic pressure were all significantly higher in obese fa/fa rats than in lean counterparts, which were prevented by CR. Magnetic resonance imaging revealed that the increase in LV end-systolic volume, stroke volume and LV wall thickness observed in fa/fa rats was significantly lower in animals on CR diet. Histological analysis also revealed that CR blocked the significant increase in cardiomyocyte diameter in obese fa/fa rats. High resolution magic angle spinning magnetic resonance spectroscopy analysis of the LV revealed a global decrease in metabolites such as taurine, creatine and phosphocreatine, glutamate, glutamine and glutathione, in obese fa/fa rats, whereas lactate concentration was increased. By contrast, fatty acid concentrations in LV tissue were significantly elevated in obese fa/fa rats. CR failed to restore the LV metabolomic profile of obese fa/fa rats. In conclusion, mild and short-term CR prevented an obesity-induced cardiomyopathy phenotype in young obese fa/fa rats independently of the cardiac metabolic profile.This study was supported by grants from Spanish Ministry of Science and Innovation (BFU2011-25303), Spanish Institute of Health Carlos III (CP15/00129), UCM groups (GR-921641), SESCAMET, Fundación Mutua Madrileña, Fundación Eugenio Rodríguez Pascual and Fondos FEDER.Peer Reviewe

Dental implants placed on bone subjected to vertical alveolar distraction show the same performance as those placed on primitive bone

Introduction: Vertical osteogenic alveolar distraction (VOAD) allows for the augmentation of the alveolar ridge for the placement of dental implants in atrophic alveolar ridges. The goal of this paper is to assess long-term peri- implant bone resorption in implants placed on bones subjected to VOAD, comparing it with a group of patients who had implants placed directly on the alveolar bone without previous bone regeneration. Material and Methods: We conducted a follow-up study on 32 patients who were divided into two groups: The Distraction Group (14 patients), and the Distraction-Free Group (18 patients), who received a total of 100 implants. Peri-implant bone loss was measured by means of panoramic X-rays, at the time of loading and one year later, and in 35 implants of each group after 3 years of functional loading. Results: The peri-implant bone resorption (PBR) average observed in the Distraction Group at the time of prosthetic placement is higher (0.50±0.09 mm) than in the Distraction-Free Group (0.25±0.06 mm), showing statistically significant results (p=0.047). PBR levels 1 year after loading were the same for both groups (0.66 mm). At 3 years, they were higher in the Distraction Group (1.03 ± 0.22 mm vs. 0.68 ± 0.08 mm)

Imbalance between pro and anti-oxidant mechanisms in perivascular adipose tissue aggravates long-term high-fat diet-derived endothelial dysfunction

Background: The hypothesis of this study is that long-term high-fat diets (HFD) induce perivascular adipose tissue (PVAT) dysfunction characterized by a redox imbalance, which might contribute to aggravate endothelial dysfunction in obesity. Methods and Results: C57BL/6J mice were fed either control or HFD (45% kcal from fat) for 32 weeks. Body weight, lumbar and mesenteric adipose tissue weights were significantly higher in HFD animals compared to controls. The anticontractile effect of PVAT in mesenteric arteries (MA) was lost after 32 week HFD and mesenteric endothelial-dependent relaxation was significantly impaired in presence of PVAT in HFD mice (Emax = 71.0±5.1 vs Emax = 58.5±4.2, p<0.001). The inhibitory effect of L-NAME on Ach-induced relaxation was less intense in the HFD group compared with controls suggesting a reduction of endothelial NO availability. Expression of eNOS and NO bioavailability were reduced in MA and almost undetectable in mesenteric PVAT of the HFD group. Superoxide levels and NOX activity were higher in PVAT of HFD mice. Apocynin only reduced contractile responses to NA in HFD animals. Expression of ec-SOD and total SOD activity were significantly reduced in PVAT of HFD mice. No changes were observed in Mn-SOD, Cu/Zn-SOD or catalase. The ratio [GSSG]/([GSH]+[GSSG]) was 2-fold higher in the mesenteric PVAT from HFD animals compared to controls. Conclusions: We suggest that the imbalance between pro-oxidant (NOX, superoxide anions, hydrogen peroxide) and antioxidant (eNOS, NO, ecSOD, GSSG) mechanisms in PVAT after long-term HFD might contribute to the aggravation of endothelial dysfunctionThis work was supported by grants from Ministerio de Ciencia e Investigación (BFU2011-25303), Ministerio de Economía y Competitividad (SAF2009- 09714, SAF2011-25303, BFU2012-35353), Grupos Universidad Complutense de Madrid (UCM; GR-921641), Fundación Universitaria San Pablo-CEU, Fundación Mutua Madrileña and Sociedad para el Estudio de la Salud Cardiometabólica (SESCAMET). MGO and CFG-P are supported by Ministerio de Educación y Cienci

Anticontractile Effect of Perivascular Adipose Tissue and Leptin are Reduced in Hypertension

Leptin causes vasodilatation both by endothelium-dependent and -independent mechanisms. Leptin is synthesized by perivascular adipose tissue (PVAT). The hypothesis of this study is that a decrease of leptin production in PVAT of spontaneously hypertensive rats (SHR) might contribute to a diminished paracrine anticontractile effect of the hormone. We have determined in aorta from Wistar-Kyoto (WKY) and SHR (i) leptin mRNA and protein levels in PVAT, (ii) the effect of leptin and PVAT on contractile responses, and (iii) leptin-induced relaxation and nitric oxide (NO) production. Leptin mRNA and protein expression were significantly lower in PVAT from SHR. Concentration-response curves to angiotensin II were significantly blunted in presence of PVAT as well as by exogenous leptin (10−9 M) only in WKY. This anticontractile effect was endothelium-dependent. Vasodilatation induced by leptin was smaller in SHR than in WKY, and was also endothelium-dependent. Moreover, release of endothelial NO in response to acute leptin was higher in WKY compared to SHR, but completely abolished in the absence of endothelium. In conclusion, the reduced anticontractile effect of PVAT in SHR might be attributed to a reduced PVAT-derived leptin and to an abrogated effect of leptin on endothelial NO release probably due to an impaired activation of endothelial NO synthase

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 obesity15 página

Mechanisms of Perivascular Adipose Tissue Dysfunction in Obesity

Most blood vessels are surrounded by adipose tissue. Similarly to the adventitia, perivascular adipose tissue (PVAT) was considered only as a passive structural support for the vasculature, and it was routinely removed for isolated blood vessel studies. In 1991, Soltis and Cassis demonstrated for the first time that PVAT reduced contractions to noradrenaline in rat aorta. Since then, an important number of adipocyte-derived factors with physiological and pathophysiological paracrine vasoactive effects have been identified. PVAT undergoes structural and functional changes in obesity. During early diet-induced obesity, an adaptative overproduction of vasodilator factors occurs in PVAT, probably aimed at protecting vascular function. However, in established obesity, PVAT loses its anticontractile properties by an increase of contractile, oxidative, and inflammatory factors, leading to endothelial dysfunction and vascular disease. The aim of this review is to focus on PVAT dysfunction mechanisms in obesity

Differential Deleterious Impact of Highly Saturated Versus Monounsaturated Fat Intake on Vascular Function, Structure, and Mechanics in Mice

Vegetable oils such as palm oil (enriched in saturated fatty acids, SFA) and high-oleic-acid sunflower oil (HOSO, containing mainly monounsaturated fatty acids, MUFA) have emerged as the most common replacements for trans-fats in the food industry. The aim of this study is to analyze the impact of SFA and MUFA-enriched high-fat (HF) diets on endothelial function, vascular remodeling, and arterial stiffness compared to commercial HF diets. Five-week-old male C57BL6J mice were fed a standard (SD), a HF diet enriched with SFA (saturated oil-enriched Food, SOLF), a HF diet enriched with MUFA (unsaturated oil-enriched Food, UOLF), or a commercial HF diet for 8 weeks. Vascular function was analyzed in the thoracic aorta. Structural and mechanical parameters were assessed in mesenteric arteries by pressure myography. SOLF, UOLF, and HF diet reduced contractile responses to phenylephrine and induced endothelial dysfunction in the thoracic aorta. A significant increase in the β-index, and thus in arterial stiffness, was also detected in mesenteric arteries from the three HF groups, due to enhanced deposition of collagen in the vascular wall. SOLF also induced hypotrophic inward remodeling. In conclusion, these data demonstrate a deleterious effect of HF feeding on obesity-related vascular alterations that is exacerbated by SFA