[Portosinusoidal vascular disorder: A paradigm shift]. / Enfermedad vascular portosinusoidal: un cambio de paradigma.

The term portosinusoidal vascular disorder (PSVD) refers to a clinical-pathological entity that encompasses those patients with intrahepatic vascular damage without cirrhosis at risk of developing severe complications of portal hypertension. Numerous systemic diseases, genetic disorders, and toxic agents have been associated with this pathology, making its diagnosis an important clinical challenge. The recent description of uniform diagnostic criteria and a better understanding of its pathophysiology will allow for better identification of patients, even in early stages of the disease. Although there is currently no effective etiological treatment available, early diagnosis allows for the development of preventive strategies for some severe complications of portal hypertension.

The Effect of Diet on Cardiovascular Disease, Heart Disease, and Blood Vessels.

The Effect of Diet on Cardiovascular Disease, Heart Disease, and Blood Vessels [...].

Rationale and design of the BA-SCAD (Beta-blockers and Antiplatelet agents in patients with Spontaneous Coronary Artery Dissection) randomized clinical trial.

INTRODUCTION Y OBJECTIVES: Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome. Most patients are empirically treated with beta-blockers and antiplatelet drugs. The Beta-blockers and Antiplatelet agents in patients with Spontaneous Coronary Artery Dissection (BA-SCAD) is an academic, pragmatic, prospective, randomized, open-label, blinded-endpoint clinical trial, performed under the auspices of the Spanish Society of Cardiology, to assess the efficacy of pharmacological therapy in patients with SCAD. METHODS: Using a 2 x 2 factorial design, 600 patients will be randomized (1:1/1:1) to: a) beta-blockers (yes/no) and b) "short" (1 month) vs "prolonged" (12 months) antiplatelet therapy. Only patients with preserved left ventricular ejection fraction will be randomized to beta-blockers (yes/no) because patients with reduced left ventricular ejection fraction will receive beta-blockers according to current guidelines. Similarly, only conservatively managed patients (ie, no coronary intervention) will be randomized to the antiplatelet stratum, as patients requiring coronary interventions will receive 1-year dual antiplatelet therapy. The primary efficacy endpoint includes a composite of death, myocardial infarction, stroke, coronary revascularization, recurrent SCAD, and unplanned hospitalization for acute coronary syndrome or heart failure at 1 year. The primary safety endpoint will be bleeding. All patients will be clinically followed up yearly. A comprehensive set of additional substudies (clinical, imaging, revascularization, biomarkers, inflammatory, immunologic, pharmacogenetics, and genetic) will be conducted to ensure a holistic view of this unique and challenging clinical entity. CONCLUSIONS: The results of the BA-SCAD randomized clinical trial will advance our knowledge in the treatment of patients with SCAD. The study was registered at ClinicalTrials.gov (Identifier: NCT04850417).

TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy.

BACKGROUND: Coronary allograft vasculopathy (CAV) is a devastating sequela of heart transplant in which arterial intimal thickening limits coronary blood flow. There are currently no targeted therapies to prevent or reduce this pathology that leads to transplant failure. Vascular smooth muscle cell (VSMC) phenotypic plasticity is critical in CAV neointima formation. TET2 (TET methylcytosine dioxygenase 2) is an important epigenetic regulator of VSMC phenotype, but the role of TET2 in the progression of CAV is unknown. METHODS: We assessed TET2 expression and activity in human CAV and renal transplant samples. We also used the sex-mismatched murine aortic graft model of graft arteriopathy (GA) in wild-type and inducible smooth muscle-specific Tet2 knockout mice; and in vitro studies in murine and human VSMCs using knockdown, overexpression, and transcriptomic approaches to assess the role of TET2 in VSMC responses to IFNγ (interferon γ), a cytokine elaborated by T cells that drives CAV progression. RESULTS: In the present study, we found that TET2 expression and activity are negatively regulated in human CAV and renal transplant samples and in the murine aortic graft model of GA. IFNγ was sufficient to repress TET2 and induce an activated VSMC phenotype in vitro. TET2 depletion mimicked the effects of IFNγ, and TET2 overexpression rescued IFNγ-induced dedifferentiation. VSMC-specific TET2 depletion in aortic grafts, and in the femoral wire restenosis model, resulted in increased VSMC apoptosis and medial thinning. In GA, this apoptosis was tightly correlated with proliferation. In vitro, TET2-deficient VSMCs undergo apoptosis more readily in response to IFNγ and expressed a signature of increased susceptibility to extrinsic apoptotic signaling. Enhancing TET2 enzymatic activity with high-dose ascorbic acid rescued the effect of GA-induced VSMC apoptosis and intimal thickening in a TET2-dependent manner. CONCLUSIONS: TET2 is repressed in CAV and GA, likely mediated by IFNγ. TET2 serves to protect VSMCs from apoptosis in the context of transplant vasculopathy or IFNγ stimulation. Promoting TET2 activity in vivo with systemic ascorbic acid reduces VSMC apoptosis and intimal thickening. These data suggest that promoting TET2 activity in CAV may be an effective strategy for limiting CAV progression.

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.

Post-treatment with yiqifumai injection and its main ingredients attenuates lipopolysaccharide-induced microvascular disturbance in mesentery and ileum.

OBJECTIVE: To investigate the effect of Yiqifumai injection (YQFM), a compound Chinese medicine, and its main active ingredients on lipopolysaccharide (LPS)-induced microvascular disturbance in mesentery and ileum. METHODS: Rats were infused with LPS (5 mg/kg/h) for 90 min. Thirty minutes after initiation of LPS administration, YQFM (160 mg/kg/h), Rb1 (5 mg/kg/h), Sch (2.5 mg/kg/h), or Rb1+Sch (5 mg/kg/h + 2.5 mg/kg/h) was infused until 90 min. Human umbilical vein endothelial cells (HUVECs) were incubated with LPS (100 ng/ml) for 90 min. YQFM (1 mg/ml), Rb1 (100 µM), Sch (100 µM), or Rb1+Sch (200 µM) was added 30 min after initiation of LPS stimulation. RESULTS: Yiqifumai injection and Rb1+Sch inhibited mesenteric venule hyperpermeability, suppressed microvillar erosion and submucosal edema, and protected claudin-5 from downregulation and interleukin-1ß from upregulation in ileal tissues after LPS. Study in HUVECs confirmed the effect of YQFM and Rb1+Sch on JAM-1 after LPS and revealed a similar effect on other junction proteins. Moreover, YQFM and Rb1+Sch attenuated the dysfunctional energy metabolism and the activation of TLR-4/Src/NF-κB signaling with Rb1 and Sch being partially effective. CONCLUSION: These results demonstrated the beneficial effect of post-treatment with YQFM, which is attributable to its main ingredient Rb1 and Sch, and likely mediated by targeting TLR-4/Src/NF-κB signaling pathway.

Outcomes of an Emergency Department Observation Unit-Based Pathway for the Treatment of Uncomplicated Vaso-occlusive Events in Sickle Cell Disease.

STUDY OBJECTIVE: This was a prospective, pre-post, 13-year observational study documenting the multiyear implementation of an observation unit sickle cell pathway for patients with uncomplicated vaso-occlusive events. METHODS: The sickle cell pathway begins with rapid triage to identify patients with uncomplicated vaso-occlusive events for immediate transfer to the observation unit and initiation of patient-controlled analgesia followed by repeated evaluations of pain and identification of other complications. Data were abstracted from the electronic medical record or observation unit database. The sickle cell pathway was initiated in April 2006. Major revisions of it were carried out in June 2009 (physician evaluation occurs in sickle cell pathway and only patient-controlled analgesia administration of medications) and October 2010 (multidisciplinary management and individual dosing). RESULTS: Annual ED visits ranged between 287 and 528. The preimplementation hospital admission rate was 33% (123/368), 3-day return rate 16% (60/368), and 30-day return rate 67% (248/368). Refinements to the sickle cell pathway have resulted in a decrease in admission rate to 20% (258/1276); 3-day return rate, to 3.6% (46/1,276); and 30-day return rate, to 41% (525/1,276) for the past 3 years. CONCLUSION: The use of a sickle cell pathway for the treatment of uncomplicated vaso-occlusive events has been effective in providing rapid treatment and reducing hospital admissions. However, it was not only the intervention and its refinement that made the sickle cell pathway successful. With the Consolidated Framework for Implementation Research, it was discerned that outer setting factors of organizational commitment to the care of patients with SCD, inner setting factors of learning climate and leadership engagement, individuals, and process contributed to the success of the sickle cell pathway.

Efficacy and safety of shenqi compound for the treatment of diabetic macroangiopathy: A protocol for systematic review and meta-analysis.

BACKGROUND: Diabetic macroangiopathy is a further complication of diabetes mellitus and is the leading cause of death for diabetic patients. Shenqi compound (SC) is a traditional Chinese medicine formula widely used in the treatment of diabetes and diabetic macroangiopathy. At present, there is only 1 systematic review on SC in the treatment of diabetes. However, no meta-analysis has evaluated the efficacy and safety of SC on diabetic macroangiopathy. METHODS AND ANALYSIS: Three English database and four Chinese medical databases will be searched from its inception to February 2020. Then 2 methodological trained researchers will screen the qualified articles by reading the title, abstract, and full texts according to an established inclusion and exclusion criteria. The assessment of risk of bias will be conducted by using the Cochrane collaboration's tool. We will conduct meta-analyses for fasting blood glucose (FBG), postprandial blood glucose (PBG), glycated hemoglobin (HbA1c), and other outcomes. The heterogeneity of data will be evaluated by Cochrane χ and I tests. We establish 3 hypotheses before the subgroup analysis actually starts: disease status at baseline, duration of intervention, type of concomitant medication. We will conduct sensitivity analysis to evaluate the stability of the results, funnel plot analysis, and Egger test to evaluate the publication bias, and assessment for the quality of evidence by the Grading of Recommendations Assessment, Development, and Evaluate system (GRADE). RESULTS: The results will be published at a peer-reviewed journal. CONCLUSION: In this study, we will systematically evaluate the evidence of SC in the treatment of diabetic macroangiopathy. Our research is supposed to provide evidence-based support for clinical practice.

Carnitine Profile Changes in Pediatric Hematopoietic Stem Cell Transplant: New Role for Carnitine?

Carnitine is an essential cofactor for mitochondrial import and oxidation of fatty acids. High-dose chemotherapy and radiation, often required for hematopoietic stem cell transplant (HSCT), leads to tissue damage, mitochondrial dysfunction, and alterations in carnitine metabolism. The aim of this pilot cohort study was to describe plasma and urinary carnitine profiles during pediatric HSCT and their relationships with clinical outcomes. Plasma and urinary carnitine samples were collected from 22 pediatric patients before and through day 180 post-HSCT. Associations were observed between graft-versus-host disease and an elevated plasma total carnitine (P=0.019), and also increased plasma acyl:free carnitine ratio with veno-occlusive disease (P=0.016). Mortality was observed in those with their highest urinary total carnitine losses on day 0 (P=0.005), and in those with an abnormal day 28 plasma ratio either above or below the reference range (P=0.007). Changes in carnitine profiles were more reflective of metabolic stress and negative outcomes than of inadequate dietary intake. Associations observed direct larger studies to assess the validity of carnitine profiles as a prognostic indicator and also to assess whether prophylactic carnitine supplementation pre-HSCT could reduce mitochondrial injury and urinary losses and help mitigate inflammatory and metabolic comorbidities of HSCT.

Arginine supplementation and cardiometabolic risk.

PURPOSE OF REVIEW: Because arginine is the substrate for nitric oxide synthesis, which is pivotal to vascular homeostasis and linked to the insulin response, it has long been posited that supplemental arginine could benefit cardiometabolic health. RECENT FINDINGS: Recent data have supported the view that supplemental arginine could alleviate the initiation and development of endothelial dysfunction and also shown that it may reduce the risk of type 2 diabetes. One important finding is that these effects may indeed vary as a function of the amount of arginine, its form and notably the metabolic status of the population. Some studies have shown that low doses of slow-release arginine are better used for nitric oxide synthesis and beneficial in individuals with abnormal arginine metabolism/bioavailability. Pathophysiological data in rodents have emphasized the importance of arginase activation during the development of cardiometabolic risk, which lends credence to a potential benefit for arginine supplements. Likewise, epidemiological evidence suggests that alterations to arginine bioavailability are important regarding the cardiometabolic risk. However, other metabolic mechanisms linked to the multiple pathways of arginine metabolism may also play a role. SUMMARY: Further studies are needed to confirm and analyze how and when supplemental arginine is beneficial to cardiometabolic health.

Association of plasma homocysteine level with vaso-occlusive crisis in sickle cell anemia patients of Odisha, India.

Vascular complications of sickle cell anemia (SCA) are influenced by many factors. Elevated plasma homocysteine (Hcy) is supposed to be an independent risk factor and is either genetic or nutritional origin. The present study evaluated the plasma Hcy level, MTHFR C677T gene polymorphism, effect of folic acid (FA) supplementation' and hemato-biochemical parameters in SCA and their effect on the vaso-occlusive crisis (VOC) in SCA patients of an Asian-Indian haplotype population. One hundred twenty cases of SCA (HbSS) and 50 controls with normal hemoglobin(HbAA) were studied. It was found that the plasma Hcy level is significantly higher (p < 0.0001) in patients with SCA (22.41 ± 7.8 µmol/L) compared to controls (13.2 ± 4.4 µmol/L). Moreover, patients without FA supplementation had a significantly (p < 0.001) higher Hcy level (27 ± 7 µmol/L) compared to those with supplementation (17.75 ± 5.7 µmol/L). Turkey-Kramer multiple comparison tests show that there is a significant difference (p < 0.05) in HbF percent, hemoglobin (Hb), platelet count, serum bilirubin (direct:Bil-D and total:Bil-T), aspartate transaminase (AST), lactate dehydrogenase (LDH), and plasma Hcy levels between mild and severe VOC. Between moderate VOC and severe VOC, there was a significant difference (p < 0.05) in HbF%, Bil-D, AST, Hcy. Pearson correlation revealed that plasma Hcy had a significantly (p < 0.05) positive correlation with AST, serum bilirubin (indirect and total), LDH, jaundice, stroke, VOC per year, and hospitalization per year whereas it was inversely correlated with HbF percentage, Hb level, and FA treatment. In the study population, increased plasma Hcy level, hemolysis, and platelet activation were found to influence VOC in SCA.

Strategies to ameliorate endothelial dysfunction associated with metabolic syndrome, where are we?

There is a paucity of aggregated clinical trials on strategies of ameliorating endothelial dysfunction associated with Metabolic Syndrome (MS). We reviewed clinical trials conducted between 2008 and 2017, reporting on strategies of improving endothelial function in patients with MS. A comprehensive search of published articles by the Google Scholar and PubMed were carried out. Only studies involving non-invasive, objective measurement of endothelial function were included. Thirty (30) studies were selected for analysis, in which physical exercise training, diet modification, calcium channel blockers + alpha-lipoic acid, bezafibrate, allopurinol, mesoglycan, and l-arginine supplementation significantly improved Endothelial-Dependent Vasodilation (EDV) in patients with MS but without cardiovascular diseases. Large multicenter clinical trials are required to address the question of generalizability of these findings.

Modeling elastin-associated vasculopathy with patient induced pluripotent stem cells and tissue engineering.

Elastin-associated vasculopathies are life-threatening conditions of blood vessel dysfunction. The extracellular matrix protein elastin endows the recoil and compliance required for physiologic arterial function, while disruption of function can lead to aberrant vascular smooth muscle cell proliferation manifesting through stenosis, aneurysm, or vessel dissection. Although research efforts have been informative, they remain incomplete as no viable therapies exist outside of a heart transplant. Induced pluripotent stem cell technology may be uniquely suited to address current obstacles as these present a replenishable supply of patient-specific material with which to study disease. The following review will cover the cutting edge in vascular smooth muscle cell modeling of elastin-associated vasculopathy, and aid in the development of human disease modeling and drug screening approaches to identify potential treatments. Vascular proliferative disease can affect up to 50% of the population throughout the world, making this a relevant and critical area of research for therapeutic development.

Long-term outcome of open surgery in CVI patients concerning postoperative complications, perioperative hemodynamics and clinical efficacy, Part II1.

BACKGROUND: Chronic venous disease (CVD) is extremely common worldwide with prevalence increasing with age. It is associated with a reduced quality of life, particularly in relation to pain, physical function and mobility. Symptomatic chronic venous insufficiency (CVI) with venous ulcer at its' endpoint, indicates interventional surgery to cure venous reflux therewith promoting wound healing and preventing recurrence. In this retrospective, single-centre, consecutive case-control study in a single patient population of a university clinic in northern Germany a holistic evaluation of varicose vein surgeries has been undertaken. Part I covered postoperative complications in relation to co-morbidities, co-medication and clinical presentation. Part II of this article presents now the hemodynamic results in relation to the perioperative evolution of CVI specific symptoms. METHODS: Records of n = 429 (467 extremities) patients from 2009-2013 treated with open surgery were analysed with regards to perioperative hemodynamics. Evolution of CVI symptomology was accessed postoperatively with the help of a questionnaire and patient records in the case of complication development. Venous hemodynamics was analysed in the whole patient population and with regards to complication subgroups: no events (NE), neglectable adverse events (NAE) and non-neglectable adverse events (NNAE). RESULTS: Postoperatively, patients' CVI-symptoms like pain (p < 0.001), swelling (p < 0.001) and itching (p = 0.003) significantly improved. The venous refill time and venous pump capacity improved significantly after open vein surgery (p < 0.05). Regardless of the development of postoperative complications there was a significant improvement of venous function at 6 weeks- and one-year postoperative in follow-up (p < 0.05). Symptom regression was strongly correlated with hemodynamic improvement. CONCLUSION: A significant improvement of patients' symptoms was achieved by means of open-surgery, regardless of postoperative complication development. This was in accordance with the improvement of venous hemodynamics. A strong correlation between symptom regression and improvement in venous hemodynamics could be proven.

Pro-resolving lipid mediators in vascular disease.

Unresolved inflammation is central to the pathophysiology of commonly occurring vascular diseases such as atherosclerosis, aneurysm, and deep vein thrombosis - conditions that are responsible for considerable morbidity and mortality. Surgical or catheter-based procedures performed on affected blood vessels induce acute-on-chronic inflammatory responses. The resolution of vascular inflammation is an important driver of vessel wall remodeling and functional recovery in these clinical settings. Specialized pro-resolving lipid mediators (SPMs) derived from omega-3 polyunsaturated fatty acids orchestrate key cellular processes driving resolution and a return to homeostasis. The identification of their potent effects in classic animal models of sterile inflammation triggered interest in their vascular properties. Recent studies have demonstrated that SPMs are locally synthesized in vascular tissues, have direct effects on vascular cells and their interactions with leukocytes, and play a protective role in the injury response. Early translational work has established the potential for SPMs as vascular therapeutics, and as candidate biomarkers in vascular disease. Further investigations are needed to understand the molecular and cellular mechanisms of resolution in the vasculature, to improve tools for clinical measurement, and to better define the potential for "resolution therapeutics" in vascular patients.

Mangiferin inhibits high-fat diet induced vascular injury via regulation of PTEN/AKT/eNOS pathway.

Mangiferin (MAN), a naturally occurring polyphenol commonly found in mango and papaya. However, little is known its anti-vascular injury effects and the underlying mechanisms. This paper investigated the anti-vascular injury effect of MAN and the mechanisms in high-fat diet (HFD)-induced C57BL/6J mice and oxidized low-density lipoprotein (ox-LDL) induced human umbilical vein endothelial cells (HUVECs). The levels of plasma lipid, inflammatory factors and nitric oxide (NO) in mice were evaluated. The expression levels of PI3K, AKT, eNOS, PTEN and their phosphorylated proteins were measured by western blots. In addition, the PTEN-siRNA HUVECs were also used. The result showed that MAN markedly decreased the plasma lipid, inflammatory level in HFD-induced vascular injury mice respectively. Furthermore, MAN alleviate ox-LDL-stimulated dysfunction of HUVECs, restored the diminished NO release, decreased the ROS generation, significantly increased the expression of p-Akt, p-eNOS, and decreased the expression of PTEN, but have no effect on PI3K. However, the protective effects of MAN were significantly reduced by co-treatment with PI3K inhibitor or abolished by eNOS inhibitor. In addition, MAN has no protective effect on ox-LDL induced PTEN-siRNA HUVECs injury. Collectively, MAN appeared to alleviate ox-LDL-stimulated dysfunction of HUVECs via the PTEN/Akt/eNOS signaling pathway, thus decrease vascular injury in HFD-administrated mice.

Tetramethylpyrazine protects against high glucose-induced vascular smooth muscle cell injury through inhibiting the phosphorylation of JNK, p38MAPK, and ERK.

Objectives High glucose-induced alterations in vascular smooth muscle cell behavior have not been fully characterized. We explored the protective mechanism of tetramethylpyrazine (TMP) on rat smooth muscle cell injury induced by high glucose via the mitogen-activated protein kinase (MAPK) signaling pathway. Methods Vascular smooth muscle cells (VSMCs) isolated from rat thoracic aortas were divided into control, high glucose (HG), and pre-hatching TMP groups. The effect of different glucose concentrations on cell viability and on the migration activity of VSMC cells was examined using MTT analysis and the wound scratch assay, respectively. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured using enzyme-linked immunoassays. The levels of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38MAPK, and MAPK phosphorylation were assessed by western blotting. Results Cell proliferation was remarkably increased by increased glucose concentrations. Compared with the HG group, the migratory ability of VSMC cells was reduced in the presence of TMP. TMP also decreased the MDA content in the supernatant, but significantly increased the SOD activity. Western blotting showed that TMP inhibited the phosphorylation of JNK, p38MAPK, and ERK. Conclusions TMP appears to protect against HG-induced VSMC injury through inhibiting reactive oxygen species overproduction, and p38MAPK/JNK/ERK phosphorylation.

What the radiologist should know about postoperative MDCT evaluation of a patient treated with cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy.

Cytoreductive surgery (CRS), often associated with hyperthermic intraperitoneal chemotherapy (HIPEC), is now a well-recognised treatment for most peritoneal malignancies in selected patients. As imaging is frequently performed postoperatively, radiologists are increasingly confronted with postoperative multidetector-row computed tomography (MDCT) examinations in these cases. In this article, after briefly describing the procedures that are currently being performed for the treatment of peritoneal metastases, the normal postoperative MDCT changes that may be encountered after these procedures are described. We then highlight complications that may arise after CRS, depending on the surgery performed, and those related to HIPEC, and illustrate their MDCT features.

Docosahexaenoic acid, but not eicosapentaenoic acid, improves septic shock-induced arterial dysfunction in rats.

INTRODUCTION: Long chain n-3 fatty acid supplementation may modulate septic shock-induced host response to pathogen-induced sepsis. The composition of lipid emulsions for parenteral nutrition however remains a real challenge in intensive care, depending on their fatty acid content. Because they have not been assessed yet, we aimed at determining the respective effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) during septic shock-induced vascular dysfunction. METHODS: In a peritonitis-induced septic shock model, rats were infused with EPA, DHA, an EPA/DHA mixture or 5% dextrose (D5) during 22 hours. From H18, rats were resuscitated and monitored during 4 hours. At H22, plasma, aorta and mesenteric resistance arteries were collected to perform ex vivo experiments. RESULTS: We have shown that septic rats needed an active resuscitation with fluid challenge and norepinephrine treatment, while SHAM rats did not. In septic rats, norepinephrine requirements were significantly decreased in DHA and EPA/DHA groups (10.6±12.0 and 3.7±8.0 µg/kg/min respectively versus 17.4±19.3 µg/kg/min in D5 group, p<0.05) and DHA infusion significantly improved contractile response to phenylephrine through nitric oxide pathway inhibition. DHA moreover significantly reduced vascular oxidative stress and nitric oxide production, phosphorylated IκB expression and vasodilative prostaglandin production. DHA also significantly decreased polyunsaturated fatty acid pro-inflammatory mediators and significantly increased several anti-inflammatory metabolites. CONCLUSIONS: DHA infusion in septic rats improved hemodynamic dysfunction through decreased vascular oxidative stress and inflammation, while EPA infusion did not have beneficial effects.

Effect of apple polyphenols on vascular oxidative stress and endothelium function: a translational study.

SCOPE: We aimed examining apple polyphenols' effect on uricemia and endothelial function in a sample of overweight subjects. METHODS AND RESULTS: This was a two-phased study. In vitro experiment aimed to evaluate apple polyphenols' ability to lower uric acid in comparison with allopurinol. In vivo study consisted in a randomized, double-blind, parallel placebo-controlled clinical trial involving 62 overweight volunteers with suboptimal values of fasting plasma glucose (100 mg/dL≤FPG≤125 mg/dL), randomized to 300 mg apple polyphenols or placebo for 8 weeks. Apple polyphenols extract inhibited xanthine oxidase activity, with an IC50 = 130 ± 30 ng/mL; reducing uric acid production with an IC50 = 154 ± 28 ng/mL. During the trial, after the first 4 weeks of treatment, FPG decreased in the active treated group (-6.1%, p < 0.05), while no significant changes were observed regarding the other hematochemistry parameters. After 4 more weeks of treatment, active-treated patients had an improvement in FPG compared to baseline (-10.3%, p < 0,001) and the placebo group (p < 0,001). Uric acid (-14.0%, p < 0.05 versus baseline; p < 0.05 versus placebo) and endothelial reactivity (0.24±0.09, p = 0.009 versus baseline; p < 0.05 versus placebo) significantly improved too. CONCLUSION: In vivo, apple polyphenols extract has a positive effect on vascular oxidative stress and endothelium function and reduce FPG and uric acid by inhibiting xanthine oxidase, as our In vitro experiment attests.