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Background Diabetes has a pronounced effect on the peripheral vasculature. The accumulation of advanced glycation end products (AGEs) is regarded as the crucial mechanism responsible for vascular damage in diabetes, but it is not easy to be avoided from food. In this study, we aimed to investigate the effects of an oral absorbent, AST-120, on the accumulation of AGEs and changes in blood flow recovery in diabetic mice. Methods The mice were divided into four groups, wild-type (WT) mice without treatment, WT mice treated with 5% AST-120 mixed into pulverized chow, streptozotocin-induced diabetes mellitus (DM) mice, and DM mice treated with 5% AST-120. Six weeks after hind-limb ischemia surgery, blood flow reperfusion, histology, plasma AGE, and cytokine were examined. Bone marrow cells were cultured and derived into macrophages to evaluate the effects of AGEs on macrophage polarization. Results Plasma AGEs were significantly increased in diabetic mice. AST-120 could bind to AGEs and reduced their plasma concentrations. Histological analysis revealed fewer collateral vessels with corresponding impairment of blood flow recovery in diabetic mice. In these mice, AGE-positive and AGE receptor-positive macrophages were numerous in ischemic limbs compared with non- diabetic mice. In diabetic mice, macrophages in ischemic tissues demonstrated greater M1 polarization than M2 polarization; this pattern was reversed in the AST-120 treatment group. The change in macrophage polarization was associated with the corresponding expression of pro-inflammatory cytokines in the ischemic tissues. In cell cultures, AGEs triggered the transformation of bone marrow-derived macrophages into the M1 phenotype. The alterations in the polarization of macrophages were reversed after treatment with AST-120. Conclusions Oral administration of AST-120 decreased the serum levels of AGEs in diabetic mice and improved neovascularization of ischemic limbs. This benefit may be due to, at least partially, the alterations in macrophage polarization and the associated changes in inflammatory cytokines.

Background No randomized controlled trials evaluating metformin therapy efficacy in patients with type 2 diabetes mellitus (DM) and acute coronary syndrome (ACS) have been reported. We aimed to examine the mortality benefit of metformin therapy in patients with type 2 DM and ACS, compared with non-metformin anti-diabetes agents users. Methods Data were extracted from the prospective nationwide ACS-DM Taiwan Society of Cardiology registry. Propensity score (PS) matching on baseline characteristics and treatment measures was performed for metformin versus non-metformin users. The Cox proportional hazards model was used to compare mortality outcomes among the PS-matched cohort as the primary analysis. The Cox proportional hazards models adjusting for all pre-determined covariates and quintiles of the PS among the overall population were performed as the secondary analyses. Results Of 1157 patients with type 2 DM and ACS receiving anti-diabetes agents, 78 patients (6.7%) died over the 2-year follow-up period. After PS matching, 318 metformin users were matched with 318 non-metformin users. Metformin users had a lower all-cause mortality rate (adjusted hazard ratio [aHR] 0.50, 95% confidence interval [CI] 0.26–0.95) in the primary analysis. The survival benefit of metformin therapy was consistent in the secondary analyses (aHR 0.30, 95% CI 0.17–0.54 while adjusting for all pre-determined covariates, and aHR 0.34, 95% CI 0.19–0.59 while adjusting for quintiles of the PS). Conclusions Among patients with type 2 DM and ACS, metformin was associated with lower all-cause mortality. However, a detrimental effect of any of the comparators could not be excluded.

Background Hypertrophic cardiomyopathy (HCM), affecting 0.2% of the population, is the leading cause of sudden cardiac arrest (SCA). Incident atrial fibrillation (AF) is associated with an increased risk of SCA in general population. To determine whether AF is associated with an increased risk of SCA in patients with HCM. Methods This nationwide cohort study analyzed data from Registry for Catastrophic Illness, which encompassed almost 100% of the patients with HCM in Taiwan from 1996 to 2013. Follow-up and data analysis ended December 31, 2013. The main outcome was physician-adjudicated SCA, defined as death from a sudden, pulseless condition presumed due to a ventricular tachyarrhythmia. The secondary outcome was non-sudden cardiac death (NSCD), which was heart failure death, stroke death and non-HCM related death. We used Cox proportional hazards models to assess the association between AF and SCA/NSCD, adjusting for baseline demographic and cardiovascular risk factors. Findings A total 10,910 subjects participated in this study with mean age of 62 years. Among enrolled subjects, 1,169 (10.7%) developed AF, which was independently associated with elder age, female sex, and history of heart failure (HF) hospitalization. During follow-up (median, 8.5 years and 2th to 7th interquartile range, 3.6 to 16.5 years), 371 SCA (166 in AF and 205 in non-AF group) and 797 NSCD (417 in AF and 380 in non-AF group) events occurred. The crude incidence rates of SCA were 12.45/1000 person-years (with AF) and 3.57/1000 person-years (without AF). The crude incidence rates for NSCD were 31.29/1000 person-years (with AF) and 6.63/1000 person-years (without AF). The multivariable hazard ratios (HRs) (95% CI) of AF for SCA and NSCD were 3.633 (2.756–4.791) and 2.086 (1.799–2.418), respectively. Furthermore, among the etiologies of NSCD, subjects with AF was at most risk of stroke-related death (HR, 6.609; 95% CI, 3.794–9.725). Interpretation Incident AF is associated with an increased risk of SCA and NSCD in the HCM population. Early detection of AF may provide more comprehensive risk stratification of SCD in HCM population. Because of underuse of oral anticoagulants and the absence of primary prevention ICD therapy in our cohort, the application of our findings was limited for the general HCM population in the current clinical practice. Funding None

Anesthetics, particularly volatile anesthetics, have been shown to impair glucose metabolism and cause hyperglycemia, closely linking them with mortality and morbidity as related to surgery. Beyond being an anesthetic used for general anesthesia and sedation, intravenous hypnotic propofol displays an effect on glucose metabolism. To extend the scope of propofol studies, its effects on glucose metabolism were evaluated in male Sprague-Dawley rats of various ages. Unlike chloral hydrate and isoflurane, propofol had little effect on basal glucose levels in rats at 2 months of age, although it did reduce chloral hydrate- and isoflurane-induced hyperglycemia. Propofol reduced postload glucose levels after either intraperitoneal or oral administration of glucose in both 7- and 12-month-old rats, but not those at 2 months of age. These improved effects regarding propofol on glucose metabolism were accompanied by an increase in insulin, fibroblast growth factor-21 (FGF-21), and glucagon-like peptide-1 (GLP-1) secretion. Additionally, an increase in hepatic FGF-21 expression, GLP-1 signaling, and FGF-21 signaling, along with a decrease in endoplasmic reticulum (ER) stress, were noted in propofol-treated rats at 7 months of age. Current findings imply that propofol may turn into insulin-sensitizing molecules during situations of existing insulin resistance, which involve FGF-21, GLP-1, and ER stress.

Ischemic stroke provokes an inflammatory response concurrent with both sympathetic nervous system activation and hyperglycemia. Currently, their crosstalk and consequences in stroke outcomes are of clinical attraction. We have provided experimental evidence showing the suppressive effects of the nonselective &beta, adrenoreceptor antagonist propranolol on hyperglycemia, inflammation, and brain injury in a rat model experiencing cerebral ischemia. Pretreatment with propranolol protected against postischemic brain infarction, edema, and apoptosis. The neuroprotection caused by propranolol was accompanied by a reduction in fasting glucose, fasting insulin, glucose tolerance impairment, plasma C-reactive protein, plasma free fatty acids, plasma corticosterone, brain oxidative stress, and brain inflammation. Pretreatment with insulin alleviated&mdash, while glucose augmented&mdash, postischemic brain injury and inflammation. Additionally, the impairment of insulin signaling in the gastrocnemius muscles was noted in rats with cerebral ischemia, with propranolol improving the impairment by reducing oxidative stress and tumor necrosis factor-&alpha, signaling. The anti-inflammatory effects of propranolol were further demonstrated in isoproterenol-stimulated BV2 and RAW264.7 cells through its ability to decrease cytokine production. Despite their potential benefits, stroke-associated hyperglycemia and inflammation are commonly linked with harmful consequences. Our findings provide new insight into the anti-inflammatory, neuroprotective, and hypoglycemic mechanisms of propranolol in combating neurodegenerative diseases, such as stroke.

Background: After angioplasty, veins are more prone to intimal hyperplasia than arteries. Veins tend to produce less nitric oxide (NO), which could lead to endothelial dysfunction. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase and contributes to cardiovascular disease. In humans, dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the major enzyme for ADMA degradation. In this study, we aim to determine whether venous intimal hyperplasia in hemodialysis (HD) vascular access is influenced by common polymorphisms in the DDAH1 genes. Methods: This is a prospective observational cohort study. A total of 473 HD patients referred for the angioplasty of vascular access were enrolled. There were 190 arteriovenous grafts (AVG) and 283 arteriovenous fistulas (AVF). The follow-up lasted for 2 years after the interventions. Seven single nucleotide polymorphisms (SNPs) in DDAH1 were genotyped and ADMA were measured at baseline. The primary outcome was restenosis after angioplasty. Results: Among the 7 SNPs, plasma ADMA levels were significantly different in DDAH1 rs233112 (GA + GG vs. AA, 0.86 ± 0.23 vs. 0.82 ± 0.19 μM, p = 0.03) and rs1498373 (CT + TT vs. CC, 0.87 ± 0.23 vs. 0.82 ± 0.20 μM, p = 0.02) genotypes. The AVF group with GG + GA genotype of rs233112 and CT + TT genotype of rs1498373 had higher risks of early restenosis at 3 months. In the AVG group, only GG + GA genotype of rs233112 was associated with early restenosis. A combined analysis of AVG and AVF groups showed that patients with rs233112 GA + GG genotype and rs1498373 CT + TT genotype had higher risks of early restenosis (both p < 0.001). The multivariate analysis results showed that the association of these genotypes with early restenosis is independent of clinical, access, or biochemical factors. Conclusions: Our findings suggest that certain DDAH1 polymorphisms modulate circulating ADMA levels and are associated with venous intimal hyperplasia.

Percutaneous transluminal angioplasty (PTA) is widely used as the primary treatment for dialysis vascular access dysfunction. Nonetheless, many patients develop early occlusion after angioplasty. Thus, we investigated the role of thrombophilia in access occlusion within 30 days of angioplasty. This case–control study included patients who underwent PTA for dialysis vascular access dysfunction. Patients who experienced occlusion within 30 days of angioplasty were included in the case group and those without occlusion for at least 30 days after angioplasty were included in the control group. All patients were tested for protein C, protein S, antithrombin III, lupus anticoagulant, and anticardiolipin antibodies. From February to October 2015, 462 patients underwent PTA for dialysis vascular access dysfunction. Forty-one patients (8.9%) had early occlusion within 30 days of angioplasty. The case group had more graft accesses (73 vs. 31%, P

Mounting evidence suggests that physical exercise shows health benefits in a range of diseases, including psychiatric disorders. Perinatal opioid exposure produces neurobehavioral abnormality, which includes depression symptoms, in patients and their offspring following chronic use of buprenorphine, a mixed agonist/antagonist with a high affinity to opioid receptors, for pain control. Previously, we demonstrated that prenatal buprenorphine exposure in pregnant Sprague-Dawley rats starting from gestation day 7 and lasting for 14 days caused the development of depression-like phenotypes in pups at postnatal day 21. Using the same prenatal buprenorphine exposure model, we further demonstrated that a 4-week course of moderate treadmill exercise conducted on pups starting from postnatal day 22 improved depression-like neurobehaviors. Prenatal buprenorphine exposure-induced neurobehavioral changes were accompanied by reductions of neuronal survival, neural stem cell-associated genes, plasma level of brain-derived neurotrophic factor (BDNF) and serotonin, phosphorylated tropomyosin-related kinase receptor type B (TrkB), phosphorylated extracellular signal-regulated kinase (ERK), PKA activity, phosphorylated cAMP response element-binding protein (CREB), and CREB DNA binding activity, as well as elevation of repressor element-1 silencing transcription factor (REST), oxidative stress, and inflammatory responses. Those changes in parameters of plasma and brain were improved by treadmill exercise. In conclusion, the findings of the current study suggest that a non-pharmacological option, i.e., moderate treadmill exercise, alleviated the development of depression-like neurobehaviors by resolving the oxidative and inflammatory burden as well as by enhancing neurochemical and neuroendocrine signaling.

CKD is an independent risk factor for cardiovascular disease (CVD). The accumulation of uremic toxins in CKD induces oxidative stress and endothelial dysfunction. MicroRNA-92a (miR-92a) is induced by oxidative stress in endothelial cells (ECs) and involved in angiogenesis and atherosclerosis. We investigated a role for oxidative stress–responsive miR-92a in CKD. Our study of patients at three clinical sites showed increased serum miR-92a level with decreased kidney function. In cultured ECs, human CKD serum or uremic toxins (such as indoxyl sulfate), compared with non-CKD serum, induced the levels of miR-92a and suppressed the expression of miR-92a targets, including key endothelial-protective molecules. The antioxidant N-acetylcysteine inhibited these vasculopathic properties. In rats, adenine-induced CKD associated with increased levels of miR-92a in aortas, serum, and CD144+ endothelial microparticles. Furthermore, CD144+ microparticles from human uremic serum contained more miR-92a than those from control serum. Additional analysis showed a positive correlation between serum levels of miR-92a and indoxyl sulfate in a cohort of patients with ESRD undergoing hemodialysis. Collectively, our findings suggest that the uremic toxins accumulated in CKD can upregulate miR-92a in ECs, which impairs EC function and predisposes patients to CVD.

Obesity is associated with a wide range of chronic diseases, including cancer. It has been noted that the integration of metabolic mechanisms in obese patients may predispose them to suffer from cancer incidence and its progression. Thus, a better understanding of metabolic alterations in obesity, along with the development of feasible therapeutic approaches for intervention, are theoretically relevant to the prevention and treatment of cancer malignancy. Using a syngeneic tumor model involving Lewis Lung Carcinoma (LLC) cells and C57BL/6 mice fed with a high fat diet, obesity was found to be associated with dysregulated glucose and glutamine metabolism, inflammation, along with platelet activation and the promotion of tumor growth. Tumor-bearing lowered glucose levels while moderately increasing inflammation, platelet activation, and glutamine levels. The antiplatelet drug aspirin, mitigated tumor growth in obese mice, paralleled by a decrease in systemic glucose, insulin, inflammation, platelet activation, glutamine and tumor expression of cell proliferation, aerobic glycolysis, glutaminolysis, platelets, and leukocyte molecules. The anti- and pro-cell proliferation, aerobic glycolysis, and glutaminolysis effects of aspirin and glutamine were further demonstrated in a LLC cell study. Although there remains limitations to our experiments, glucose and glutamine metabolism are proposed targets for the anticancer effects of aspirin.

Endovascular therapy is the principal therapy for haemodialysis vascular access dysfunction. Nonetheless, the incidence and determinants of post-intervention thrombotic events are unclear. This prospective cohort study evaluated the incidence and timing of thrombotic events after endovascular therapy and analysed the clinical, angiographic, and biological determinants of thrombosis. Of the 236 patients enrolled, 91 experienced post-intervention thrombotic events within 1 year. The 1-year thrombosis-free patency was 28% for thrombosed accesses, 53% for non-thrombosed grafts, and 78% for non-thrombosed fistulas. Forty-one of the 91 thrombotic events (45%) occurred within 3 months post-intervention. In the univariate analysis, early thrombosis was associated with longer haemodialysis duration (hazard ratio [HR], 1.01; 95% confidence interval [CI], 1.01–1.02), graft access (HR, 7.69; 95% CI, 3.33–20.0), multiple stenoses (HR, 2.69; 95% CI, 1.36–5.37), and high indoxyl sulphate (IS) levels (HR, 1.55; 95% CI, 1.32–1.82). Late thrombosis was associated with diabetes (HR, 1.89; 95% CI, 1.01–3.57), cardiovascular disease (HR, 2.38; 95% CI, 1.27–4.54), and endothelial progenitor cell counts (HR, 0.97; 95% CI, 0.93–0.99). After multivariate adjustment, high IS was the major predisposing factor for early post-intervention thrombosis (HR, 1.41; 95% CI, 1.18–1.69). Our findings suggest that measures to decrease IS could target the most critical period of thrombosis.

Background The aim of this study was to determine the influence of various antidiabetic therapies on the relationship between body mass index and all‐cause mortality in patients with diabetes mellitus and acute coronary syndrome. Methods and Results This was a prospective, observational study comprising 1193 patients diagnosed with type 2 diabetes mellitus and acute coronary syndrome. The patients were stratified into 4 body mass index categories, and their mortality rates were compared using time‐dependent Cox regression analysis using normal weight (body mass index, 18.5–23.9) as the reference. Subsequently, the influence of antidiabetic therapies on the association between BMI and mortality were analyzed. Seventy‐four patients (6.2%) died over 2 years of follow‐up. The mortality rate was lowest in the class I obese group (3.35%) and highest in the normal‐weight group (9.67%). After adjusting for covariates, class I obesity paradoxically remained significantly protective against mortality compared with normal weight (hazard ratio, 0.141; P =0.049); interaction term analysis showed that insulin therapy influenced this “obesity paradox” ( P =0.045). When the patients were stratified by insulin use, the protective effect of obesity disappeared in the insulin‐treated patients but persisted in the non–insulin‐treated patients. Conclusions In patients with type 2 diabetes mellitus and acute coronary syndrome, the relationship between body mass index and mortality rate is U‐shaped, with class I obesity representing the nadir and normal weight the peak. The protective effect of obesity disappeared in patients treated with insulin.

Background Hemodialysis (HD) patients have an increased risk of thrombosis. Endothelial progenitor cells (EPCs), which function in vascular repair, are deficient in HD patients. Nonetheless, the relationship between EPC deficiency and thrombosis in HD patients is unknown. Methods From January 2010 to December 2012, circulating levels of EPCs that were positive for CD34 and kinase insert domain receptor (KDR) were measured in 269 HD patients. Patients received prospective follow-ups at 6-month intervals until May 2015. The primary outcome was the composite of HD access thrombosis and systemic vascular thrombosis. Results There were 141 thrombotic events, 50 systemic vascular thrombotic events and 116 HD access thrombotic events. We found significantly negative associations between CD34 + KDR + tertile and overall thrombotic events (low: 61%; middle: 56%; high: 40%; P = 0.02), systemic vascular thrombotic events (low: 27%; middle: 18%; high: 10%; P = 0.03) and HD access thrombotic events (low: 52%; middle: 46%; high: 36%; P = 0.02). Univariate analysis indicated that systemic vascular thrombotic events were positively associated with age, diabetes, dyslipidemia, vascular disease history, urea clearance, albumin and C-reactive protein (CRP), and negatively associated with CD34 + KDR + cell count. HD access thrombosis was positively associated with vascular disease history and CRP, and negatively associated with CD34 + KDR + cell count. Multivariate analysis indicated that a low CD34 + KDR + cell count was an independent risk factor for both types of thrombosis. Conclusions Our study of a population of HD patients showed that a low level of circulating EPCs is associated with thrombosis.

Contains fulltext : 215333.pdf (Publisher’s version ) (Closed access) BACKGROUND: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor. METHODS: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population). FINDINGS: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3.3 years (IQR 2.8-3.8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7.3%] of 5558 vs 480 [8.6%] of 5596; HR 0.85 [95% CI 0.74-0.97], p=0.013). The same effect was not observed in patients without PCI (p=0.76, pinteraction=0.16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3.1%] with ticagrelor vs 183 (3.3%) with placebo; HR 0.96 [95% CI 0.78-1.18], p=0.68), as well as all-cause death (282 [5.1%] vs 323 [5.8%]; 0.88 [0.75-1.03], p=0.11). TIMI major bleeding occurred in 111 (2.0%) of 5536 patients receiving ticagrelor and 62 (1.1%) of 5564 patients receiving placebo (HR 2.03 [95% CI 1.48-2.76], p

Background Parenteral anticoagulants and vitamin K antagonists (VKAs) have constituted the cornerstone of venous thromboembolism (VTE) treatment. Meanwhile, direct oral anticoagulants (DOACs) provide physicians with an alternative. The Global Anticoagulant Registry in the FIELD (GARFIELD)-VTE observes real-world treatment practices. Objectives Describe initial anticoagulation (AC) treatment patterns in VTE patients who received parenteral AC, VKAs, and/or DOACs within ±30 days of diagnosis. Methods VTE patients were categorized into parenteral AC only, parenteral AC with transition to VKA, VKA only, parenteral AC with transition to DOAC, and DOAC only. Results A total of 9647 patients were initiated on AC treatment alone. 4781 (49.6%) patients received DOACs ± parenteral ACs; 3187 (33.0%), VKA ± parenteral ACs; and 1679 (17.4%) parenteral ACs alone. Rivaroxaban was the most frequently used DOAC (79.4%). DOACs were more frequently used in North America/Australia (58.1%), Europe (52.2%), and Asia (47.6%) than in Latin America (29.7%) and the Middle East/South Africa (32.5%). In patients with suspected VTE, most received parenteral AC monotherapy (67.7%). Patients with deep vein thrombosis were more likely to receive DOACs alone than those with pulmonary embolism with or without deep vein thrombosis (36.2% vs 25.9%). Active cancer patients received parenteral AC alone (58.9%), with 25.5% receiving DOAC ± parenteral AC and 12.8% parenteral AC and VKA. A total of 46.5% of pregnant patients received parenteral AC monotherapy, 34.0% were treated with VKA ± parenteral AC, and 19.5% received a DOAC (± parenteral AC). Conclusion AC treatment patterns vary by patient population, geographic region and site of VTE. Guidelines for AC therapy are not always adhered to.

Background: No randomized controlled trials evaluating metformin therapy efficacy in patients with type 2 diabetes mellitus (DM) and acute coronary syndrome (ACS) have been reported. Well-designed retrospective studies controlling for imbalance in baseline patient characteristics are scarce. We aimed to examine the mortality benefit of metformin therapy in patients with type 2 DM and ACS, compared with non-metformin anti-diabetes agent users. Method: Data were extracted from the prospective nationwide ACS-DM Taiwan Society of Cardiology registry. Propensity score (PS) matching on baseline characteristics and treatment measures was performed for metformin versus non-metformin users. Cox proportional hazard models were used to compare mortality outcomes among the PS-matched cohort as a primary analysis. Traditional Cox proportional hazard models adjusting for all pre-determined covariates and quintiles of the PS among the overall population were performed as a secondary analysis. Findings: Of 1157 patients with type 2 DM and ACS receiving anti-diabetes agents, 78 patients (6.7%) died over the 2-year follow-up period. After PS matching, 318 metformin users were matched with 318 non-metformin users. Metformin users had a lower all-cause mortality rate (adjusted hazard ratio [aHR] 0·50, 95% confidence interval [CI] 0·26-0·95) in the primary analysis. The survival benefit of metformin therapy was consistent in the secondary analyses (aHR 0·30, 95% CI 0·17-0·54 while adjusting for all pre-determined covariates, and aHR 0·34, 95% CI 0·19-0·59 while adjusting for quintiles of the PS). Interpretation: Among patients with type 2 DM and ACS, metformin was associated with lower all-cause mortality. Funding Statement: This work was supported with grants from the Hsin-Chu branch of the National Taiwan University Hospital (HCH-106036). The funding source also provided technical help (Biotechnology R&D Center) with data analysis and interpretation of the findings. Declaration of Interest: All authors report no relationships that could be construed as a conflict of interest. Ethics Approval Statement: Patients are treated according to international or local guidelines and evidence-based strategies. The protocol and consent forms used in this study were consistent with the Declaration of Helsinki and relevant regulations. The ethics committees of each participating hospital approved the study, and all enrolled patients provided written informed consent.

// I-Chun Chen 1 , Chin-Sung Kuo 1, 2 , Chih-Cheng Wu 3, 4, 5, 6 , Hsiao-Ya Tsai 1 , Chih-Pei Lin 7, 8 , Szu-Yuan Li 1, 9 , Ruey-Hsing Chou 1, 3, 10 , Po-Hsun Huang 1, 3, 10 , Jaw-Wen Chen 3, 10, 11, 12 and Shing-Jong Lin 1, 3, 10, 11, 13 1 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 2 Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 3 Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan 4 National Tsing-Hua University, Institute of Biomedical Engineering, Hsinchu, Taiwan 5 National Taiwan University Hospital, College of Medicine, Taipei, Taiwan 6 Cardiovascular Center, National Taiwan University Hospital, Hsinchu Branch, Hsinchu, Taiwan 7 Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 8 Department of Biotechnology and Laboratory Science in Medicine and Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei, Taiwan 9 Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 10 Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 11 Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan 12 Institute and Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan 13 Taipei Medical University, Taipei, Taiwan Correspondence to: Po-Hsun Huang, email: huangbsvgh@gmail.com Chih-Cheng Wu, email: chihchengwumd@gmail.com Chin-Sung Kuo, email: cskuo241@yahoo.com.tw Keywords: hyperuricemia; endothelial progenitor cell; ischemia; neovascularization Received: August 14, 2017 Accepted: January 02, 2018 Published: January 22, 2018 ABSTRACT Objective: Chronic hyperuricemia is associated with cardiovascular disease, but its impact on endothelial progenitor cells (EPC) and ischemia-induced neovascularization remains unclear. Herein we investigated whether chronic hyperuricemia could impede blood flow recovery in response to tissue ischemia by suppression of EPC. Methods: Human EPC were isolated and cultured in a high-level uric acid medium for functional testing. Cell proliferation, nitric oxide (NO) production and apoptosis assay were examined. A chronic hyperuricemia mouse model was established by potassium oxonate treatment and/or a high-level uric acid diet to evaluate the actions of chronic hyperuricemia on ischemia-induced blood flow recovery. After 4 weeks of drug treatment, hindlimb ischemia surgery was performed in the control and hyperuricemia mice. Blood flow recovery was followed up every week before and after ischemic surgery using a laser Doppler Perfusion Imager System. The circulating EPC number in the peripheral blood was determined by flow cytometry (Sca-1 + /Flk-1 + ). Results: Incubation with a high-level uric acid medium (10 mg/dL) significantly suppressed EPC proliferation, reduced NO production, and lessened phosphorylation of Akt and eNOS. Moreover, EPC treated with high-level uric acid increased reactive oxygen species production, promoted cellular apoptosis and senescence, and also inhibited EPC tube formation. Four weeks after hindlimb ischemia surgery, the chronic hyperuricemia mice had significantly reduced tissue reperfusion, EPC mobilization, and impaired neovascularization in the ischemic hindlimbs compared with the control mice. Conclusions: Chronic hyperuricemia impaired blood flow recovery and EPC mobilization in response to tissue ischemia, and these effects could have occurred through suppression of EPC.

Background and aim Atrial fibrillation (AF) is an important cardiovascular disease in the elderly. The association between hyperuricemia and AF is unclear. Therefore, we aimed to investigate the prospective relationship between uric acid and development of AF in a nationally representative cohort of elderly people. Methods and results A total of 1485 elderly people (age ≥ 65 yrs) from the Elderly Nutrition and Health Survey in Taiwan (1999–2000) were without AF on “electrocardiography” at baseline. Incident AF events (International Classification of Diseases, Ninth Revision, Clinical Modification, ICD-9-CM: 427.31) were identified using data from the National Health Insurance Dataset. Hyperuricemia was defined as levels of uric acid >7.0 mg/dL in men and 6.0 mg/dL in women. A Cox proportional hazards model was used to evaluate the association between hyperuricemia and incident AF. The follow-up period was from 1999 to 2000 to 2008. During the follow-up period (median: 9.16 yrs), 90 AF events occurred (44 in men and 46 in women). Older age, elevated systolic blood pressure, being an ex-smoker, and high uric acid were positively associated with incident AF. Hyperuricemia was positively associated with incident AF in normotensive (age-adjusted hazard ratio (HR): 2.65 and 95% confidence intervals: 1.05–6.69), but not in (1.20:0.74–1.94) hypertensive individuals (systolic blood pressure ≥130 or diastolic blood pressure ≥85 or using hypertensive medicine). A significant association between hyperuricemia and AF (3.78; 1.24–11.59) remained after adjusting for other potential confounders among normotensive older persons. Conclusion Hyperuricemia is associated with the development of AF in elderly people with normal blood pressure.

BackgroundPrescription of guideline-recommended medicines after acute coronary syndrome (ACS) has been suboptimal. Tools for improving the use of medications have been developed, but they mainly targeted physicians.ObjectiveWe evaluated the effects of reinforcement of patient and family education on the usage of guideline-recommended secondary prevention medications.MethodsThis was a retrospective analysis of a prospectively collected registry of patients with ACS who were admitted to a regional teaching hospital in Taiwan between February 2015 and April 2017. The control group included 76 patients discharged before implementing the electronic-based patient and family education (PFE) system. The intervention group included 206 patients discharged after implementation. The primary outcome was the prescription rate of all four guideline-recommended drugs. Predictors of adherence were also evaluated.ResultsThe study cohort included 282 ACS patients (188 men and 94 women) with a mean age of 68.5 years (standard deviation, 14.2). The intervention group patients were younger, had more family history of premature cardiovascular disease, more dyslipidemia, and underwent more reperfusion therapy. The intervention group was prescribed more guideline-recommended drugs than the control group: dual antiplatelet agents, 79.61% vs. 47.37% (pConclusionsReinforcement of patient education was associated with significant improvements in physicians' adherence to guideline-recommended medical therapy after acute coronary syndrome.

Patient initials or identifier number CSC ### Relevant clinical history and physical exam A 52 y/o man with hyperlipidemia presented with exertional chest tightness and dyspnea for 1 year. He had received PCI with a BMS implanted in LAD one year ago in a local hospital; however, his chest

Chronic kidney disease (CKD) is now clearly recognized as a public health problem worldwide. Patients with CKD display a substantial increase in end‐stage renal disease (ESRD) and cardiovascular disease (CVD).[1][1] Moreover, the prognosis of CVD in CKD is extremely poor.[2][2] Understanding the

Background: Arteriovenous fistula (AVF) thrombosis is a relevant cause of morbidity in hemodialysis (HD) patients. The number of circulating endothelial progenitor cells (EPCs) has been identified as a surrogate marker for vascular repair and health. Deficiency of EPCs has been demonstrated in dialysis patients to be associated with vascular events. Nonetheless, their role in thrombosis of AVFs remains unknown. Methods: From January 2010 to May 2013, 147 HD patients with dysfunctional AVFs were enrolled. Surface makers including CD34, KDR and CD133 were used in combination to determine the number of circulating EPCs. All participants were prospectively followed at 6-month interval until December 2015. The primary outcome was thrombosis of dialysis AVFs. Results: The median follow-up was 47 months, within which 42 patients experienced at least one episode of AVF thrombosis. Patients with AVF thrombosis had lower CD34+KDR+ cell counts compared with patients without thrombosis (median 5 vs. 13 per 150,000 mononuclear cells, p < 0.001). Kaplan-Meier analysis demonstrated an inverse relationship between CD34+KDR+ cell count tertiles and thrombosis-free patency (59, 69 and 86% for low, middle and high tertiles; p = 0.02). Using Cox regression analysis, AVF thrombosis was predicted by baseline CD34+KDR+ cell counts (hazards ratio (HR) 0.963, 95% CI 0.928-1.000, p = 0.05) and tertiles (high vs. low, HR 3.266, 95% CI 1.380-7.728, p < 0.01). In multivariate analysis, only CD34+KDR+ cell tertiles, C-reactive protein and lesion length remained independent predictors for thrombosis. Conclusion: Our study demonstrated an independently reverse association between circulating EPCs and thrombosis of dialysis AVFs. Further studies are warranted to ascertain whether EPCs serve as a marker or a therapeutic target for AVF thrombosis.

Inflammation is relevant in restenosis of atherosclerotic vascular diseases, but its role in dialysis arteriovenous fistula remains unknown. In animal studies, upregulation of monocyte chemoattractant protein-1 has been shown in venous segments of arteriovenous fistula. We, therefore, aimed to investigate serial changes in circulating monocyte chemoattractant protein-1 after percutaneous transluminal angioplasty of dialysis arteriovenous fistulas and its relation to restenosis.Fifty-nine patients with dysfunctional arteriovenous fistulas that were referred for percutaneous transluminal angioplasty were enrolled prospectively between January of 2010 and July of 2012. Three of them were excluded due to percutaneous transluminal angioplasty failure or acute infection. Blood was sampled from arteriovenous fistulas at baseline, 2 days, 2 weeks, and 3 months after percutaneous transluminal angioplasty. Clinical follow-up was continued monthly for 3 months. Angiographic follow-up was arranged at the end of 3 months. Seventeen patients without significant stenosis were enrolled as the control group.Fifty-six patients completed clinical follow-up. Significant increases in monocyte chemoattractant protein-1 were observed at 2 days and 2 weeks (both P0.001) after percutaneous transluminal angioplasty. Twenty-three (41%) patients had symptomatic restenosis. The restenosis group had a higher percentage change in monocyte chemoattractant protein-1 levels at 2 days (median =47%; interquartile range, 27%-65% versus median =17%; interquartile range, 10%-25%; P0.001) after percutaneous transluminal angioplasty compared with the patent group. Fifty-two patients completed angiographic follow-up. A positive correlation between relative luminal loss and monocyte chemoattractant protein-1 increase at 2 days after percutaneous transluminal angioplasty was found (r=0.53; P0.001). In multivariate analysis, postangioplasty monocyte chemoattractant protein-1 increase at 2 days was an independent predictor of restenosis. Using receiver operator characteristic analysis,25% postangioplasty increase of monocyte chemoattractant protein-1 was significantly associated with restenosis after percutaneous transluminal angioplasty (hazard ratio, 5.36; 95% confidence interval, 1.81 to 15.8).Circulating monocyte chemoattractant protein-1 levels were elevated 2 days and 2 weeks after percutaneous transluminal angioplasty. Early postangioplasty increase of monocyte chemoattractant protein-1 level was associated with restenosis of arteriovenous fistulas.

There is an ongoing discussion on whether serum uric acid (SUA) predicts ischemic heart disease (IHD) independently of other metabolic factors, which, if confirmed, would signify a role for uric acid in the pathogenesis of cardiovascular disease. We investigated whether such a relation exists for ethnic Chinese with low CVD risk.Enrolled, between 1994 and 1996, were 128,569 adults ≥ 20 years from four 'MJ' Health Check-up Clinics in Taiwan. Excluded were those with heart disease, previous stroke(s), renal disease, and/or cancer. Physical examinations, biospecimen collections, and structured questionnaires were executed according to standardised protocols. We identified IHD events according to the ICD-9-CM codes 410-414 using hospitalisation records obtained from the National Health Insurance and the Death Certification Registry databases. The Cox proportional hazard model was used to estimate the hazard ratios (HRs) between SUA and IHD events. A total of 2049 subjects (1239 men, 810 women) developed IHD from baseline to Dec. 31, 2002. Men had a higher IHD incidence than did women (2.84 vs. 1.61 1/1000 person-years; p0.0001). The risk-factor-adjusted HRs (95% confidence-interval [CI]) for hyperuricemiae (SUA ≥ 7.0/≥ 6.0mg/dL) were 1.25 (1.11-1.40) for men and 1.19 (1.02-1.38) for women. In the low-risk population (lacking the NCEP-ATPIII metabolic syndrome components), a significant association was still observed (adjusted HR: 1.54 [1.09-2.17]).The hyperuricemia was independently associated with the development of IHD not only in the general population but also in those without any metabolic risk factor for NCEP ATPIII. Hyperuricemia may be considered as a potential risk factor for IHD.

Thrombophilia has been proposed to be an important risk factor hemodialysis vascular access thrombosis. Nonetheless, the role of thrombophilia on post-angioplasty thrombosis remained unknown. From Jan 2015 to Dec 2015, a nested case-control study was performed in patients who received endovascular

Plasma levels of asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide production, correlate with endothelial dysfunction and the development of cardiovascular events in patients with uremia. It is not known whether endothelial dysfunction contributes to the dysfunction of arteriovenous fistulas (AVFs) in hemodialysis patients. Here, we studied the predictive value of baseline plasma ADMA for symptomatic restenosis of an AVF after percutaneous transluminal angioplasty in dialysis patients. We obtained baseline plasma ADMA levels before percutaneous transluminal angioplasty in 100 consecutive patients with dysfunctional AVFs. Patients were followed up clinically for up to 6 mo after angioplasty for recurrent dysfunction. During the 6 mo after angioplasty, 46 patients experienced recurrent dysfunction of their AVF; of these, follow-up fistulography showed restenosis at the same location in 41, new stenosis at different locations in two, and no significant stenosis in three patients. Up to 60% of the patients with high levels of ADMA (>0.910 microM) had target lesion restenosis compared with 25% of those with low levels (

Background: Before this study, the efficacy and safety of doubling the dosage of fluvastatin from 40 mg/day to 80 mg/day in Chinese patients with primary hypercholesterolemia remained to be determined. Methods: In this open-label, active-controlled randomized 2-center study, patients with primary hypercholesterolemia were randomized to treatment with immediate-release fluvastatin 40 mg/day (n = 30) or slow-release fluvastatin 80 mg/day (n = 31) for 12 weeks. The primary efficacy variable was percent change in low-density lipoprotein (LDL) cholesterol level from baseline. Secondary efficacy variables were percent changes in total cholesterol, triglyceride, and high-density lipoprotein (HDL) cholesterol levels, and the percent of patients achieving LDL cholesterol goals of the US National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) II. Results: Both fluvastatin dosages (40 mg/day vs 80 mg/day) effectively reduced LDL cholesterol (-22.5% vs -29.9%; p = 0.087), total cholesterol (-17.3% vs -22.5%; p = 0.140), and triglyceride levels (-14.0% vs -12.3%; p = 0.813) (all p < 0.0001 for comparison with baseline), and slightly increased HDL cholesterol levels (+5.2% vs +5.6%; p = 0.917), after 12 weeks of treatment. The percent of patients achieving LDL cholesterol goals of the NCEP ATP II was 37% versus 65% (p < 0.05). The adverse event profiles for the 2 fluvastatin dosages were similar. Conclusion: In Chinese patients with primary hypercholesterolemia, doubling the dosage of fluvastatin from 40 to 80 mg once daily was effective and safe regarding reduction of LDL cholesterol level, and allowed more patients to achieve LDL cholesterol goals of the NCEP ATP II. (J Chin Med Assoc 2005;68(8):353-359)

A total of 32 patients without regional wall motion abnormality of the left ventricle underwent sequential tissue Doppler echocardiography and cardiac catheterization. Peak velocities of systolic (Sa), early diastolic (Ea), and late diastolic (Aa) motion of the mitral annulus were measured. Normal references for Sa, Ea and Aa were obtained from 138 volunteers. Indices of left ventricular (LV) systolic and diastolic function were evaluated using high-fidelity LV pressure and volume signals. By multivariate analysis, Sa, Ea and As were significantly and independently related to the maximum of the first derivative of pressure over time (dP/dt max ), LV relaxation time constant (τ), and LV ejection fraction (EF), respectively. Using the fifth percentiles of the age-stratified normal references as cut-offs, low Sa, low Ea and low Aa identified declined dP/dt max , prolonged τ and reduced EF, respectively, with good sensitivities and specificities. In conclusion, mitral annulus velocities by tissue Doppler echocardiography can be used to identify patients with declined dP/dt max , prolonged τ and reduced EF. (E-mail: chench@vghtpe.gov.tw)

In end-stage renal disease (ESRD) patients undergoing regular haemodialysis (HD), the maintenance of fluid status within an optimal range is critical. We therefore examined the role of Doppler echocardiographic parameters in the assessment of fluid status in these patients.Three study groups were enrolled: 40 healthy volunteers (NTNR), 40 HD patients who were normotensive without receiving antihypertensive agents (NTHD) and 38 HD patients who had remained hypertensive (HTHD) despite antihypertensive treatment. Measurements of Doppler echocardiographic parameters from pulmonary vein (PV) and mitral inflow (Mi) were performed on a non-dialysis day. Extracellular water as a percentage of body weight (ECW%) and pre-dialysis mean blood pressure (BDMBP) were references for fluid status. The best Doppler parameter for fluid status assessment identified from the study groups was then tested in another validation groups (38 NTHD and 38 HTHD).Among all of the PV and Mi parameters, the S/D ratio (peak systolic velocity divided by peak diastolic velocity) was correlated with fluid status parameters best (with ECW%, r = -0.49, P0.001; with BDMBP, r = -0.51, P0.001). The correlations were independent of age, sex and Mi parameters. The receiver operating characteristics curve analysis demonstrated that an S/D ratio1.33 had a sensitivity of 90% and a specificity of 77% in identifying NTHD patients. When the same criterion was applied to the validation groups, the positive predictive value was 64% and the negative predictive value was 86%.The Doppler-derived S/D ratio is a potentially useful marker for the assessment of fluid status in HD patients.

Background: Patient-activated event re- corders are useful for the diagnosis of arrhythmia in patients with palpitation and presyncope. However, the utility of event recorders in patients suspected of arrhythmia but presenting with other symptoms is not clear. Furthermore, the factors influencing their utility have not been evaluated.

Pulmonary vein Doppler spectrum is highly load-dependent and thus has been used to estimate left ventricular (LV) filling pressure. However, the impact of LV function on pulmonary vein Doppler spectrum remains obscure because only load-sensitive indices were studied previously. In the present study, measurements of the pulmonary vein Doppler spectrum were correlated with load-insensitive LV systolic (end-systolic elastance [Ees]) and diastolic (relaxation time constant [tau] and beta coefficient of the end-diastolic pressure volume relationship) function indices obtained from an invasive catheterization study nonsimultaneously. The peak velocity, velocity time integral, and duration of systolic forward spectrum were significantly correlated with Ees (r = 0.35, r = 0.36, andr = 0.41, respectively;P < 0.05). The pulmonary vein diastolic velocity time integral (PVDVTI) and duration of the diastolic forward spectrum were significantly correlated with Ees (r = 0.51andr = 0.57, respectively;P < 0.01). PVDVTI was correlated with tau and the end-diastolic pressure-volume relationship (EDPVR) (r = 0.42andr = 0.40respectively,P < 0.05). On the other hand, the systolic fraction of the forward spectrum was significantly correlated with ejection fraction (for peak velocity,r = 0.63, P < 0.01; for velocity time integral,r = 0.37, P < 0.05) but not with Ees, and the diastolic fraction of the forward spectrum was significantly correlated with minimum pressure derivative over time (for peak velocity,r = 0.48, P < 0.05; for velocity time integral,r = 0.44, P < 0.05, respectively) but not with tau or EDPVR. In summary, the systolic and diastolic components of the pulmonary vein Doppler spectrum are affected variably by LV systolic and diastolic function, independent of the loading condition. The systolic and diastolic fraction of pulmonary vein Doppler spectrum appears to depend more on the loading condition than the LV systolic or diastolic function. (ECHOCARDIOGRAPHY, Volume 20, January 2003)

The left ventricular (LV) end-systolic pressure-volume relation (ESPVR) is a load-insensitive method for evaluating LV contractility, which needs invasive measurement. Some noninvasive methods substitute peak aortic pressure (Ps) for end-systolic LV pressure by assuming there is no difference between these pressures. However, this assumption has not been directly validated. With conductance catheter and dual micromanometers, ESPVRs and the slope (EesLv) were constructed from simultaneous LV pressures (LVP) and volumes, aortic pressures (AOP) and LV volumes (Ees(AO)), and Ps and LV end-ejection volumes (VEE) (Ees(PP-EEV)) during preload reduction in 50 subjects. The ratio of steady-state P(s) over V(EE) (P(S)/V(EE)) was also checked. AOP and LVP displayed differences of 11 +/- 6 and -30 +/- 12 mm Hg at the onset and end-ejection, respectively, and -2 +/- 4 mm Hg at end-systole. Ees(AO) and Ees(LV) were nearly identical: Ees(AO) = 0.97 x Ees(LV) + 0.05, r2 = 0.99. Ees(PP-EEV) correlated with EesLV (EesPP-EEV = 0.57 x EesLV + 0.61, r2 = 0.46) but with much more scatter. Ps/V(EE) correlated worst with Ees(LV). Central AOP can be substituted for LVP to derive EesLV. Other estimation methods yield weaker and poor correlations to directly measured Ees.

ObjectiveWe prospectively investigate the relation between baseline circulating endothelial progenitor cells and the subsequent development of restenosis after angioplasty of hemodialysis vascular access.BackgroundEffect of angioplasty for hemodialysis vascular access is greatly attenuated by early and frequent restenosis. Circulating endothelial progenitor cells (EPCs) play a key role in vascular repair but are deficient in hemodialysis patients.MethodAfter excluding 14 patients due to arterial stenosis, central vein stenosis, and failed angioplasty, 130 patients undergoing angioplasty for dysfunctional vascular access were prospectively enrolled. Flow cytometry with quantification of EPC markers (defined as CD34+, CD34+KDR+, CD34+KDR+CD133+) in peripheral blood immediately before angioplasty procedures was used to assess circulating EPC numbers. Patients were followed clinically for up to one year after angioplasty.ResultsDuring the one-year follow-up, 95 patients (73%) received interventions for recurrent access dysfunction. Patients in the lower tertile of CD34+KDR+ cell count had the highest restenosis rates (46%) at three month (early restenosis), compared with patients in the medium and upper tertiles of CD34+KDR+ cell count (27% and 12% respectively, p = 0.002). Patients in the lower tertile of CD34+KDR+ cell count received more re-interventions during one year. Patients with early restenosis had impaired EPC adhesive function and increased senescence and apoptosis. In multivariate analysis, the CD34+KDR+ and CD34+KDR+CD133+ cell counts were independent predictors of target-lesion early restenosis.ConclusionOur results suggest that the deficiency of circulating EPCs is associated with early and frequent restenosis after angioplasty of hemodialysis vascular access.

Purpose Vascular access thrombosis is a common complication of arteriovenous dialysis grafts that results in silent pulmonary embolism (PE) in a substantial proportion of patients. However, the impact of repeated PE on the pulmonary vasculature remains unclear. Materials and Methods From January 2010 to April 2012, 110 patients undergoing maintenance hemodialysis via arteriovenous grafts were recruited. Hemodynamic assessments, including transthoracic echocardiography and right heart catheterization, were performed at baseline and after 1 year to evaluate the changes in pulmonary artery (PA) pressures and heart function. Results Fifty-two patients completed the follow-up hemodynamic assessment at a median duration of 535 days and had at least one endovascular thrombectomy procedure (median of seven). There was no significant difference in mean PA pressures between baseline and the end of follow-up (23.1 mm Hg ± 6.8 vs 21.6 mm Hg ± 6.1; P = .16). The change in mean PA pressure did not correlate with the number of thrombectomy procedures in the overall cohort ( r = −0.02, P = .89) or in the subgroup with cardiopulmonary disease ( r = −0.30, P = .14). The changes of mean PA pressure were not associated with number of thrombectomy procedures (β = −0.03, P = .89). Conclusions Repeated endovascular thrombectomy procedures are not related to changes in PA pressure in the short term. The present results support the safety of endovascular thrombectomy in the pulmonary vasculature.

Although hemodialysis vascular access dysfunction is often caused by venous stenosis, stenosis can occur anywhere in the circuit. Herein, we report a 75-year-old woman who received repeated percutaneous angioplasty due to insufficient flow. Finally, a culprit stenosis at the subclavian artery was found and treated. Subclavian artery stenosis is often atherosclerotic in origin and is usually delayed to be diagnosed because of caveats in the care of vascular access. This case highlights important clues that can assist in the early discovery of inflow problems and reminds the physician that inflow stenosis may be hidden at a site far from the anastomosis.

Rutin has been shown to possess beneficial health effects, including hepatoprotection. However, to date, it has not been demonstrated to have a hepatoprotective effect against cholestatic liver injury. This is the first report to show a protective effect of rutin on cholestatic liver injury. Cholestasis was produced by bile duct ligation (BDL) in male Sprague-Dawley rats for 3 weeks. Daily oral administration of rutin was started 1 week before injury and was maintained for 4 weeks. In comparison with the control group, the BDL group showed liver injury as evidenced by histological changes and elevation in serum biochemicals, ductular reaction, fibrosis, inflammation, and oxidative stress. These pathophysiological changes were attenuated by rutin supplementation. Rutin alleviated BDL-induced transforming growth factor β1 (TGF-β1), interleukin-1β, connective tissue growth factor, and collagen expression. The antifibrotic effect of rutin was accompanied by reductions in α-smooth muscle actin-positive matrix-producing cells and Smad2/3 activity critical to the fibrogenic potential of TGF-β1. Rutin attenuated BDL-induced oxidative stress, leukocyte accumulation, NF-κB activation, and proinflammatory cytokine production. Further studies demonstrated an inhibitory effect of rutin on the redox-sensitive intracellular signaling molecule extracellular signal-regulated kinase (ERK). Rutin also attenuated BDL-induced reduction in NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and AMP-activated protein kinase (AMPK). Taken together, the beneficial effects of rutin were shown to be associated with antioxidative and anti-inflammatory effects as well as the downregulation of NF-κB and TGF-β/Smad signaling, probably via interference of ERK activation and/or enhancement of Nrf2, HO-1, and AMPK activity.

Patients with chronic kidney disease (CKD) have an increased risk of vascular disease, which is associated with considerable health care costs. Vascular disease in CKD differs clinically and pathobiologically from that in patients with normal renal function. Besides the traditional risk factors, retention of uremic toxins contributes to the pathogenesis of vascular disease in patients with CKD. Indoxyl sulfate is a protein-bound uremic toxin and is inefficiently removed by conventional dialysis. Accumulating evidence suggests that indoxyl sulfate is a vascular toxin involved in atherosclerosis, arteriosclerosis, vascular calcification and vascular repair. Clinically, indoxyl sulfate is associated with total and cardiovascular mortality in patients with CKD. Recent studies have indicated that in addition to coronary and cerebral arteries, indoxyl sulfate plays a role in peripheral artery disease (PAD) and dialysis graft thrombosis. Emerging evidence suggests that indoxyl sulfate is implicated via novel mechanisms, including progenitor cell-related neovascularization and tissue factor-related hypercoagulability. These findings raise the possibility that strategies targeting serum indoxyl sulfate may have the potential to improve the outcomes of PAD and dialysis vascular access in patients with CKD.

Current guidelines recommend getting a 12-lead electrocardiogram (ECG) within 10 minutes after the arrival of Emergency Department for patients with ST elevation myocardial infarction (STEMI). Previous quality–improving activities in our hospital revealed that failing to target door-to-ECG time

We used the polymerase chain reaction (PCR) to study the presence and typing of human papillomavirus (HPV) DNA, and PCR/single-strand confirmation polymorphism to survey the mutations of the p53 gene in exons 5-9 in 26 bulky stage IB cervical cancers. The HPV DNA was present in 20 out of the 21 (95%) squamous-cell carcinoma tissues, including 13 cases of HPV-16, 0 case of HPV-18, and 7 cases of other HPV types. In the other 5 adenocarcinoma tissues, 3 had HPV type-18 DNA and 2 had no detectable HPV DNA. The distribution of HPV DNA in bulky tumors was not statistically different from that in the other 228 squamous-cell carcinomas and 23 adenocarcinomas of smaller size operated upon during the same period. Out of the 26 patients, 9 (35%) had lymph node metastasis at the time of operation. During the follow-up period ranging from 19 to 48 months, 9 patients had recurrence and 7 of them died of disease. The distribution of HPV types was not related to the prognosis in these patients. There were no p53 mutations detected in all the 26 samples. Thus, HPV type and the status of p53 could not serve as additional prognostic factors in stage IB bulky cervical cancers.

Objective The aim of the study was to evaluate the role of atherosclerosis risk factors and baseline inflammatory status in the development of restenosis after successful percutaneous transluminal angioplasty (PTA) of hemodialysis arteriovenous (AV) fistulas. Research design and methods We obtained baseline plasma biochemistry and inflammatory markers in 140 patients with dysfunctional AV fistulas before the PTA procedures. Patients were followed clinically for 6 months. Results There was no significant difference in the baseline inflammatory markers between the restenosis and patency group. The Kaplan–Meier analysis showed that non-diabetic patients had higher patency rate than diabetic patients (69% vs. 48%, p =0.02) and diabetic patients with optimal glycemic control had higher patency rate than patients with suboptimal glycemic control (61% vs. 30%, p =0.01). Conclusions The presence of diabetes mellitus predicted restenosis of AV fistulas after PTA and optimal blood glucose control might be critical to the patency after PTA.

Objective Angiopoietin-like protein 2 (ANGPTL2), which is mainly expressed from adipose tissue, is demonstrated to be involved in obesity, metabolic syndrome, and atherosclerosis. Because several adipocytokines are known to be associated with heart failure (HF), here we investigated the association of ANGPTL2 and HF in Taiwanese subjects. Methods and Results A total of 170 symptomatic HF patients and 130 age- and sex-matched controls were enrolled from clinic. The echocardiography was analyzed in each patient, and stress myocardial perfusion study was performed for clinical suspicion of coronary artery disease. Detailed demographic information, medications, and biochemical data were recorded. Circulating adipocytokines, including tumor necrosis factor-alpha (TNF-α), adiponectin, adipocyte fatty acid-binding protein (A-FABP) and ANGPTL2, were analyzed. Compared with the control group subjects, serum ANGPTL2 concentrations were significantly higher in HF group patients. In correlation analyses, ANGPTL2 level was positively correlated to creatinine, fasting glucose, triglyceride, hsCRP, TNF-α, NT-proBNP and A-FABP levels, and negatively correlated with HDL-C and left ventricular ejection fraction. In multiple regression analysis, A-FABP, hsCRP, and HDL-C levels remained as independent predictors for ANGPTL2 level. To determine the association between serum ANGPTL2 concentrations and HF, multivariate logistic regression analyses were performed with subjects divided into tertiles by ANGPTL2 levels. For the subjects with ANGPTL2 levels in the highest tertile, their risk of HF was about 2.97 fold (95% CI = 1.24–7.08, P = 0.01) higher than those in the lowest tertile. Conclusion Our results demonstrate a higher circulating ANGPTL2 level in patients with HF, and the upregulating ANGPTL2 levels might be associated with metabolic derangements and inflammation.

A recent study has demonstrated that the pulsatility of the ascending aorta is a strong predictive factor for restenosis after coronary angioplasty. However, whether the pulsatility of the ascending aorta is still a significant predictor for restenosis in elderly patients with a stiffer aorta is unknown. We investigated the relation between arterial pulsatility in the ascending aorta and restenosis after coronary angioplasty in patients aged60 years. Eighty-seven consecutive patients (80 men, aged 72.5 +/- 5.1 years) with stable angina were included. Before angioplasty, the arterial systolic, diastolic, and mean pressure waveforms of the ascending aorta were measured. We used fractional pulse pressure (PPf, the ratio of pulse pressure to mean pressure) and pulsatility index (PI, the ratio of pulse pressure to diastolic pressure) to estimate the pulsatility of the ascending aorta. Angiographic restenosis occurred in 39 patients. Pulse pressure, PPf, and PI were significantly higher in patients with restenosis after coronary angioplasty (restenosis vs without restenosis: pulse pressure, 77.6 +/- 12.2 vs 66.1 +/- 15.4 mm Hg [p0.001]; PPf, 0.80 +/- 0.09 vs 0.69 +/- 0.11 [p0.001]; PI, 1.19 +/- 0.20 vs 0.98 +/- 0.21 [p0.001]). After multivariate stepwise adjustment of risk factors of restenosis and using receiver-operating characteristic analysis, the odds ratio (OR) of restenosis was: pulse pressure66 mm Hg, OR 5.88 (95% confidence interval [CI] 2.17 to 15.93); PPf0.72, OR 13.71 (95% CI 4.81 to 39.05); PI1.06, OR 13.56 (95% CI 4.67 to 39.38). Moreover, among patients aged70 years (n = 60), the predictive values of PPf and PI were even higher than those in patients agedor = 70 years (n = 27). Thus, in elderly patients with stable angina, the pulsatility of the ascending aorta is a powerful predictor of restenosis after coronary angioplasty.

Studies indicate that perinatal opioid exposure produces a variety of short- and long-term neurobehavioral consequences. However, the precise modes of action are incompletely understood. Buprenorphine, a mixed agonist/antagonist at the opioid receptors, is currently being used in clinical trials for managing pregnant opioid addicts. This study provides evidence of depression-like consequence following prenatal exposure to supra-therapeutic dose of buprenorphine and sheds light on potential mechanisms of action in a rat model involving administration of intraperitoneal injection to pregnant Sprague-Dawley rats starting from gestation day 7 and lasting for 14 days. Results showed that pups at postnatal day 21 but not the dams had worse parameters of depression-like neurobehaviors using a forced swimming test and tail suspension test, independent of gender. Neurobehavioral changes were accompanied by elevation of oxidative stress, reduction of plasma levels of brain-derived neurotrophic factor (BDNF) and serotonin, and attenuation of tropomyosin-related kinase receptor type B (TrkB) phosphorylation, extracellular signal-regulated kinase (ERK) phosphorylation, protein kinase A activity, cAMP response element-binding protein (CREB) phosphorylation, and CREB DNA-binding activity. Since BDNF/serotonin and CREB signaling could orchestrate a positive feedback loop, our findings suggest that the induction of oxidative stress, reduction of BDNF and serotonin expression, and attenuation of CREB signaling induced by prenatal exposure to supra-therapeutic dose of buprenorphine provide evidence of potential mechanism for the development of depression-like neurobehavior.

A 77-year-old man developed fever, dyspnoea, and bilateral lung oedema over a 3 days course. Echocardiography found an elongated hyperechoic mass protruding from the aortic wall near left coronary cusp, oscillating in the aortic root ( Panel A , Supplementary material online, Video S1 ). No significant valvular dysfunction or intra-cardiac thrombus was found. The blood cultures grew methicillin-resistant Staphylococcus aureus . Despite of adequate antibiotics coverage, the patient progressed into …

Background Adipokines, including adipocyte fatty acid-binding protein (A-FABP), have been demonstrated to be involved in the pathogenesis of atherosclerosis. In the present study, we investigated the association of circulating A-FABP level with severity of myocardial perfusion abnormalities analyzed by Tl-201 dipyridamole single-photon emission computed tomography. Methods A total of 170 patients with coronary artery disease (CAD) from cardiovascular clinics were enrolled in the study. Serum A-FABP levels, echocardiography, and stress myocardial perfusion imaging results were analyzed. Results Compared with the patients with mild CAD (summed stress score [SSS] ≤ 8), those with moderate to severe CAD (SSS > 8) had significantly higher A-FABP concentrations. However, the difference was attenuated in the subgroup of patients with heart failure. In the correlation analyses, A-FABP level was correlated with age, body mass index, waist circumference, levels of creatinine, fasting glucose, high-sensitivity C-reactive protein, N-terminal pro-brain natriuretic peptide, adiponectin, and several echocardiographic parameters, including left ventricular ejection fraction. Multivariate logistic regression analysis demonstrated that the A-FABP level was not only associated with higher SSS (odds ratio, 1.30; 95% confidence interval [CI], 1.01–1.69; P = 0.048), but also an independent risk factor for heart failure (odds ratio 2.71, 95% CI, 1.23–5.94; P = 0.013). Conclusions Serum A-FABP levels not only were associated with myocardial perfusion abnormalities and left ventricular function, but also predicted the presence of heart failure in our patients with CAD.