Publications by authors named "Chih-Cheng Wu"

115 Publications

TNF-α Receptor Inhibitor Alleviates Metabolic and Inflammatory Changes in a Rat Model of Ischemic Stroke.

Antioxidants (Basel) 2021 May 26;10(6). Epub 2021 May 26.

Department of Medical Research, Taichung Veterans General Hospital, Taichung City 407, Taiwan.

Hyperglycemia and inflammation, with their augmented interplay, are involved in cases of stroke with poor outcomes. Interrupting this vicious cycle thus has the potential to prevent stroke disease progression. Tumor necrosis factor-α (TNF-α) is an emerging molecule, which has inflammatory and metabolic roles. Studies have shown that TNF-α receptor inhibitor R-7050 possesses neuroprotective, antihyperglycemic, and anti-inflammatory effects. Using a rat model of permanent cerebral ischemia, pretreatment with R-7050 offered protection against poststroke neurological deficits, brain infarction, edema, oxidative stress, and caspase 3 activation. In the injured cortical tissues, R-7050 reversed the activation of TNF receptor-I (TNFRI), NF-κB, and interleukin-6 (IL-6), as well as the reduction of zonula occludens-1 (ZO-1). In the in vitro study on bEnd.3 endothelial cells, R-7050 reduced the decline of ZO-1 levels after TNF-α-exposure. R-7050 also reduced the metabolic alterations occurring after ischemic stroke, such as hyperglycemia and increased plasma corticosterone, free fatty acids, C reactive protein, and fibroblast growth factor-15 concentrations. In the gastrocnemius muscles of rats with stroke, R-7050 improved activated TNFRI/NF-κB, oxidative stress, and IL-6 pathways, as well as impaired insulin signaling. Overall, our findings highlight a feasible way to combat stroke disease based on an anti-TNF therapy that involves anti-inflammatory and metabolic mechanisms.
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http://dx.doi.org/10.3390/antiox10060851DOI Listing
May 2021

Semiparametric mixture cure model analysis with competing risks data: Application to vascular access thrombosis data.

Stat Med 2021 May 21. Epub 2021 May 21.

College of Medicine, National Taiwan University, Taipei, Taiwan, R.O.C.

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http://dx.doi.org/10.1002/sim.9036DOI Listing
May 2021

Atrial fibrillation and the risk of sudden cardiac arrest in patients with hypertrophic cardiomyopathy - A nationwide cohort study.

EClinicalMedicine 2021 Apr 17;34:100802. Epub 2021 Mar 17.

College of Medicine, National Taiwan University, Taipei, Taiwan.

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.
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http://dx.doi.org/10.1016/j.eclinm.2021.100802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102675PMC
April 2021

Endoplasmic Reticulum Stress Contributes to Gefitinib-Induced Apoptosis in Glioma.

Int J Mol Sci 2021 Apr 11;22(8). Epub 2021 Apr 11.

Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan.

Adequate stress on the Endoplasmic Reticulum (ER) with the Unfolded Protein Response (UPR) could maintain glioma malignancy. Uncontrolled ER stress, on the other hand, predisposes an apoptosis-dominant UPR program. We studied here the proapoptotic actions of the Epidermal Growth Factor Receptor (EGFR) inhibitor gefitinib, with the focus on ER stress. The study models were human H4 and U87 glioma cell lines. We found that the glioma cell-killing effects of gefitinib involved caspase 3 apoptotic cascades. Three branches of ER stress, namely Activating Transcription Factor-6 (ATF6), Protein Kinase R (PKR)-Like ER Kinase (PERK), and Inositol-Requiring Enzyme 1 (IRE1), were activated by gefitinib, along with the elevation of intracellular free Ca, Reactive Oxygen Species (ROS), and NADPH Oxidase2/4 (NOX2/4). Specifically, elevated IRE1 phosphorylation, Tumor Necrosis Factor (TNF) Receptor-Associated Factor-2 (TRAF2) expression, Apoptosis Signal-Regulating Kinase-1 (Ask1) phosphorylation, c-Jun N-Terminal Kinase (JNK) phosphorylation, and Noxa expression appeared in gefitinib-treated glioma cells. Genetic, pharmacological, and biochemical studies further indicated an active ROS/ER stress/Ask1/JNK/Noxa axis causing the glioma apoptosis induced by gefitinib. The findings suggest that ER-stress-based therapeutic targeting could be a promising option in EGFR inhibitor glioma therapy, and may ultimately achieve a better patient response.
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http://dx.doi.org/10.3390/ijms22083934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069544PMC
April 2021

Anti Human CX3CR1 VHH Molecule Attenuates Venous Neointimal Hyperplasia of Arteriovenous Fistula in Mouse Model.

J Am Soc Nephrol 2021 Apr 23. Epub 2021 Apr 23.

CardioMetabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.

Background: Fractalkine receptor 1 (CX3CR1) mediates macrophage infiltration and accumulation, causing venous neointimal hyperplasia (VNH)/venous stenosis (VS) in arteriovenous fistula (AVF). The effect of blocking CX3CR1 using an anti-human variable VHH molecule (hCX3CR1 VHH, BI 655088) on VNH/VS was determined using a humanized mouse in which the human () gene was knocked in (KI).

Methods: Whole-transcriptomic RNA sequencing with bioinformatics analysis was used on human stenotic AVF samples, C57BL/6J, KI mice with AVF and CKD, and in experiments to identify the pathways involved in preventing VNH/VS formation after hCX3CR1 VHH administration.

Results: Accumulation of CX3CR1 and CD68 was significantly increased in stenotic human AVFs. In C57BL/6J mice with AVF, there was increased , and gene expression, and increased immunostaining of CX3CR1 and CD68. In hCX3CR1-KI mice treated with hCX3CR1 VHH molecule (KI-A), compared with vehicle controls (KI-V), there was increased lumen vessel area and patency, and decreased neointima in the AVF outflow veins. RNA-seq analysis identified TNF- and NF-B as potential targets of CX3CR1 inhibition. In KI-A-treated vessels compared with KI-V, there was decreased gene expression of , , and ; with reduction of , NF-B, and ; decreased M1, Ly6C, smooth muscle cells, fibroblast-activated protein, fibronectin, and proliferation; and increased TUNEL and M2 staining. In cell culture, monocytes stimulated with PMA and treated with hCX3CR1 VHH had decreased , , proliferation, and migration.

Conclusions: CX3CR1 blockade reduces VNH/VS formation by decreasing proinflammatory cues.
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http://dx.doi.org/10.1681/ASN.2020101458DOI Listing
April 2021

An oral absorbent, AST-120, restores vascular growth and blood flow in ischemic muscles in diabetic mice via modulation of macrophage transition.

J Mol Cell Cardiol 2021 Jun 10;155:99-110. Epub 2021 Mar 10.

Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Cardiovascular Research Center, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. Electronic address:

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.
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http://dx.doi.org/10.1016/j.yjmcc.2021.03.001DOI Listing
June 2021

DHA attenuated Japanese Encephalitis virus infection-induced neuroinflammation and neuronal cell death in cultured rat Neuron/glia.

Brain Behav Immun 2021 03 21;93:194-205. Epub 2021 Jan 21.

Department of Medical Research, Taichung Veterans General Hospital, Taichung City, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung City, Taiwan; Ph.D. Program in Translational Medicine, College of Life Sciences, National Chung-Hsing University, Taichung City, Taiwan. Electronic address:

Japanese Encephalitis Virus (JEV) is a neurotropic virus and its Central Nervous System (CNS) infection causes fatal encephalitis with high mortality and morbidity. Microglial activation and consequences of bystander damage appear to be the dominant mechanisms for Japanese Encephalitis and complications. Docosahexaenoic acid (DHA), an essential fatty acid and a major component of brain cell membranes, possesses additional biological activities, including anti-apoptosis, anti-inflammation, and neuroprotection. Through this study, we have provided experimental evidence showing the anti-inflammatory, neuroprotective, and anti-viral effects of DHA against JEV infection in rat Neuron/glia cultures. By Neuron/glia and Neuron cultures, DHA protected against neuronal cell death upon JEV infection and reduced JEV amplification. In Neuron/glia and Microglia cultures, the effects of DHA were accompanied by the downregulation of pro-inflammatory M1 microglia, upregulation of anti-inflammatory M2 microglia, and reduction of neurotoxic cytokine expression, which could be attributed to its interference in the Toll-Like Receptor (TLR), Mitogen-Activated Protein Kinase (MAPK), and Interferon/Janus Kinase/Signal Transducers and Activators of Transcription (Stat), along with the NF-κB, AP-1, and c-AMP Response Element Binding Protein (CREB) controlled transcriptional programs. Parallel anti-inflammatory effects against JEV infection were duplicated by G Protein-Coupled Receptor (GPR120) and GPR40 agonists and a reversal of DHA-mediated anti-inflammation was seen in the presence of GPR120 antagonist, while the GPR40 was less effectiveness. Since increasing evidence indicates its neuroprotection against neurodegenerative diseases, DHA is a proposed anti-inflammatory and neuroprotective candidate for the treatment of neuroinflammation-accompanied viral pathogenesis such as Japanese Encephalitis.
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http://dx.doi.org/10.1016/j.bbi.2021.01.012DOI Listing
March 2021

Thermocatalytic hydrogen peroxide generation and environmental disinfection by BiTe nanoplates.

Nat Commun 2021 01 8;12(1):180. Epub 2021 Jan 8.

Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, 30013, Taiwan.

The highly reactive nature of reactive oxygen species (ROS) is the basis for widespread use in environmental and health-related fields. Conventionally, there are only two kinds of catalysts used for ROS generation: photocatalysts and piezocatalysts. However, their usage has been limited due to various environmental and physical factors. To address this problem, herein, we report thermoelectric materials, such as BiTe, SbTe, and PbTe, as thermocatalysts which can produce hydrogen peroxide (HO) under a small surrounding temperature difference. Being the most prevalent environmental factors in daily life, temperature and related thermal effects have tremendous potential for practical applications. To increase the practicality in everyday life, bismuth telluride nanoplates (BiTe NPs), serving as an efficient thermocatalyst, are coated on a carbon fiber fabric ([email protected]) to develop a thermocatalytic filter with antibacterial function. Temperature difference induced HO generation by thermocatalysts results in the oxidative damage of bacteria, which makes thermocatalysts highly promising for disinfection applications. Antibacterial activity as high as 95% is achieved only by the treatment of low-temperature difference cycles. The current work highlights the horizon-shifting impacts of thermoelectric materials for real-time purification and antibacterial applications.
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http://dx.doi.org/10.1038/s41467-020-20445-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794375PMC
January 2021

Pain prevalence in hospitalized patients at a tertiary academic medical center: Exploring severe persistent pain.

PLoS One 2020 7;15(12):e0243574. Epub 2020 Dec 7.

Department of Healthcare Administration, Central Taiwan University of Science and Technology, Taichung, Taiwan.

Objective: The pain prevalence of inpatients is not a well-studied medical issue in Asia. We have aimed to evaluate pain prevalence and characterize those patients who have suffered from severe, persistent pain.

Methods: We investigated pain prevalence using a quota sampling from 19 general wards during the year 2018. Using a structured questionnaire, eight interviewers visited patients at an age ≥ 20 years, and who had been staying in general wards for ≥ 3 days. Those patients were excluded if they were unable to respond to the interview questions. If they reported pain during hospitalization, the maximum pain level and the duration of pain suffered in the past 24 hours were assessed. Care-related pain was also surveyed.

Results: A total of 1,034 patients (M/F, 537/497) completed the survey. Amongst them, 719 patients (69.5%) experienced pain, with moderate and severe pain levels being 27.3% and 43%, respectively. Surgery was considered as it related to pain, including significantly severe pain. The top 3 care-related pain causes were needle pain, wound dressing, and change in position/chest percussion. Change in position/chest percussion and rehabilitation were associated with severe, persistent pain.

Conclusions: Pain is common in approximately 70% of inpatients, with surgery being associated with severe pain. Mobilization and rehabilitation may lead to severe, persistent pain. The periodic study of pain prevalence is essential in order to provide precise pain management.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243574PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721481PMC
February 2021

Clinical Feasibility of Biofunctionalized Magnetic Nanoparticles for Detecting Multiple Cardiac Biomarkers in Emergency Chest Pain Patients.

Acta Cardiol Sin 2020 Nov;36(6):649-659

Department of Internal Medicine, National Taiwan University Hospital.

Background: The rapid diagnosis of acute myocardial infarction (AMI) is a clinical and operational priority in emergency departments. Serial serum levels of cardiac biomarkers play a crucial role in the evaluation of patients presenting with acute chest pain, so that an accurate and rapidly responsive assay of cardiac biomarkers is vital for emergency departments.

Methods: Immunomagnetic reduction (IMR) has been developed for rapid and on-site assays with a small sample volume. IMR kits for three biomarkers [myoglobin, creatine kinase-MB (CK-MB), and troponin-I] have been developed by MagQu Co., Ltd., Taiwan (US patent: US20190072563A1). In this study, we examined correlations between IMR signals and biomarker concentrations. The measurement threshold of the IMR kits, dynamic ranges, interference tests in vitro, and reagent stability were tested. Clinical cases were included with serial IMR measurements to determine the time course and peak of IMR-measured cardiac biomarkers after AMI.

Results: The correlations between IMR signals and biomarker concentrations fitted well to logistic functions. The measurement thresholds of the IMR kits (1.03 × 10 ng/mL for myoglobin, 1.46 × 10 ng/mL for CK-MB, and 0.08 ng/mL for troponin-I) were much lower than the levels detected in the patients with AMI. There was no significant interference in vitro. The peak times of IMR-detected myoglobin, CK-MB, and troponin-I after AMI were 8.2 hours, 24.4 hours, and 24.7 hours, respectively.

Conclusions: IMR is an accurate and sensitive on-site rapid assay for multiple cardiac biomarkers in vitro, and may play a role in the early diagnosis of AMI. Clinical trials are needed.
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http://dx.doi.org/10.6515/ACS.202011_36(6).20200414ADOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677641PMC
November 2020

2020 Consensus Statement of the Taiwan Hypertension Society and the Taiwan Society of Cardiology on Home Blood Pressure Monitoring for the Management of Arterial Hypertension.

Acta Cardiol Sin 2020 Nov;36(6):537-561

Faculty of Medicine, National Yang-Ming University School of Medicine.

To facilitate the applications of home blood pressure (HBP) monitoring in clinical settings, the Taiwan Hypertension Society and the Taiwan Society of Cardiology jointly put forward the Consensus Statement on HBP monitoring according to up-to-date scientific evidence by convening a series of expert meetings and compiling opinions from the members of these two societies. In this Consensus Statement as well as recent international guidelines for management of arterial hypertension, HBP monitoring has been implemented in diagnostic confirmation of hypertension, identification of hypertension phenotypes, guidance of anti-hypertensive treatment, and detection of hypotensive events. HBP should be obtained by repetitive measurements based on the " " principle, which is referred to duplicate blood pressure readings taken per occasion, twice daily, over seven consecutive days. The " " principle of HBP monitoring should be applied in clinical settings, including confirmation of hypertension diagnosis, 2 weeks after adjustment of antihypertensive medications, and at least every 3 months in well-controlled hypertensive patients. A good reproducibility of HBP monitoring could be achieved by individuals carefully following the instructions before and during HBP measurement, by using validated BP devices with an upper arm cuff. Corresponding to office BP thresholds of 140/90 and 130/80 mmHg, the thresholds (or targets) of HBP are 135/85 and 130/80 mmHg, respectively. HBP-based hypertension management strategies including bedtime dosing (for uncontrolled morning hypertension), shifting to drugs with longer-acting antihypertensive effect (for uncontrolled evening hypertension), and adding another antihypertensive drug (for uncontrolled morning and evening hypertension) should be considered. Only with the support from medical caregivers, paramedical team, or tele- monitoring, HBP monitoring could reliably improve the control of hypertension.
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http://dx.doi.org/10.6515/ACS.202011_36(6).20201106ADOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677637PMC
November 2020

Endoplasmic reticulum stress and autophagy contributed to cadmium nephrotoxicity in HK-2 cells and Sprague-Dawley rats.

Food Chem Toxicol 2020 Dec 28;146:111828. Epub 2020 Oct 28.

Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan; Ph.D. Program in Translational Medicine, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan. Electronic address:

Excessive accumulation of cadmium is known to cause nephrotoxicity by targeting renal proximal tubular epithelial cells. Studies showed an essential role of autophagy in cadmium-induced nephrotoxicity; however, its underlying mechanisms accompanied by autophagy are incompletely understood. Using an HK-2 human renal proximal tubular epithelial cell line as a study model, sustained exposure of cadmium chloride (CdCl) was shown to cause cell viability loss, which was alleviated by inhibitors of autophagy but not apoptosis. Data from molecular and biochemical studies revealed an induction of autophagy proteins, intracellular acidic vesicles, and autophagic flux in CdCl-treated cells. However, there was little sign of apoptosis-related changes. Pharmacological and genetic studies indicated an elevation of Endoplasmic Reticulum (ER) stress, Forkhead Box Class O (FoxO3a), Bcl-2 Interacting Protein 3 (Bnip3), and Beclin1, as well as their involvement in cadmium-induced autophagy and autophagic cell death. Renal injury, histological changes, and molecular marker of ER stress, FoxO3a, Bnip3, and autophagy were observed in the kidney cortex of CdCl-exposed Sprague-Dawley rats. These observations indicate that ER stress, FoxO3a, Bnip3, and autophagy signaling were actively involved in cadmium-induced nephrotoxicity. Additionally, FoxO3a may act as a linking molecule to convey ER stress signals to Bnip3 and autophagy machinery upon cadmium exposure.
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http://dx.doi.org/10.1016/j.fct.2020.111828DOI Listing
December 2020

High dose escalation of intracoronary adenosine in the assessment of fractional flow reserve: A retrospective cohort study.

PLoS One 2020 15;15(10):e0240699. Epub 2020 Oct 15.

College of Medicine, National Taiwan University, Taipei, Taiwan.

Maximal hyperaemia for fractional flow reserve (FFR) may not be achieved with the current recommended doses of intracoronary adenosine. Higher doses (up to 720 μg) have been reported to optimize hyperaemic stimuli in small dose-response studies. Real-world data from a large cohort of patients is needed to evaluate FFR results and the safety of high-dose escalation. This is a retrospective study aimed to evaluate the safety and frequency of FFR ≤0.8 after high-dose escalation of intracoronary adenosine. Data were extracted from the medical databases of two university hospitals. Increasing doses (100, 200, 400, 600, and 800 μg) of adenosine were administered as intracoronary boluses until FFR ≤0.8 was achieved or heart block developed. The percentage of FFR ≤0.8 after higher-dose escalation was compared with those at conventional doses, and the predictors for FFR ≤0.8 after higher doses were analysed. In the 1163 vessels of 878 patients, 402 vessels (34.6%) achieved FFR ≤0.8 at conventional doses and 623 vessels (53.6%) received high-dose escalation. An additional 84 vessels (13.5%) achieved FFR ≤0.8 after high-dose escalation. No major complications developed during high-dose escalation. Borderline FFR (0.81-0.85) at the conventional dose, stenosis >60%, and triple-vessel disease increased the likelihood of FFR ≤0.8 after high-dose escalation, but chronic kidney disease decreased it. For vessels of borderline FFR at conventional doses, 46% achieved FFR ≤0.8 after high-dose escalation. In conclusion, High-dose escalation of intracoronary adenosine increases the frequency of FFR ≤0.8 without major complications. It could be especially feasible for borderline FFR values near the 0.8 diagnostic threshold.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240699PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561200PMC
December 2020

Use of the Viabahn covered stent for the treatment of venous rupture during interventions of dysfunctional or thrombosed hemodialysis vascular access.

J Vasc Access 2020 Oct 3:1129729820961955. Epub 2020 Oct 3.

College of Medicine, National Taiwan University, Taipei.

Background: Angioplasty-related vessel rupture is a common complication of interventions. The effect of covered stents to treat venous rupture has been evaluated in smaller series, but should be further evaluated.

Objective: To report the immediate outcomes and patency rates of a covered stent to rescue angioplasty-related venous rupture of hemodialysis vascular access.

Methods: From January 2013 to December 2018, 113 procedures complicated with vessel ruptures were retrospectively analyzed from a prospectively collected database of 8146 hemodialysis access interventions. The strategies to salvage vessel ruptures were based on the discretion of the treating physicians. Follow-up outcomes were obtained via review of the angiographic images, procedural notes, and medical and dialysis records within 12 months after the index procedures.

Results: A total of 52 vessel ruptures (21 fistulas, 31 grafts) salvaged by using Viabahn covered stents were enrolled. Vessel ruptures developed in 28 (53.8%) thrombectomy procedures. Device success was achieved in all procedures (100%) and clinical success was achieved in 50 (96.2%). The primary patency of the stent area was 66.0% at 6 months and 50.0% at 12 months. The primary patency of the entire access circuit was 27.4% at 6 months and 16.0% at 12 months. The most common cause of access circuit primary patency loss was thrombotic occlusion for graft accesses and restenosis at stent area for native accesses. Eleven vascular accesses were abandoned within 12 months after vessel ruptures, and the secondary patency rate of the entire access circuit was 78.0% at 12 months.

Conclusions: Treatment of angioplasty-induced vessel rupture of hemodialysis vascular accesses by using Viabahn covered stents has good immediate outcomes and patency results at the stent area. Nonetheless, the patency rate of entire access circuit was still below the threshold recommended by guidelines.
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http://dx.doi.org/10.1177/1129729820961955DOI Listing
October 2020

Semiparametric mixture cure model analysis with competing risks data: Application to vascular access thrombosis data.

Stat Med 2020 11 13;39(27):4086-4099. Epub 2020 Aug 13.

College of Medicine, National Taiwan University, Taipei, Taiwan, R.O.C.

The article is motivated by a nephrology study in Taiwan, which enrolled hemodialysis patients who suffered from vascular access thrombosis. After treatment, some patients were cured of thrombosis, while some may experience recurrence of either type (acute or nonacute) of vascular access thrombosis. Our major interest is to estimate the cumulative incidence probability of time to the first recurrence of acute thrombosis after therapy. Since the occurrence of one type of vascular access thrombosis precludes occurrence of the other type, patients are subject to competing risks. To account for the presence of competing risks and cured patients, we develop a mixture model approach to the regression analysis of competing-risks data with a cure fraction. We make inference about the effects of factors on both the cure rate and cumulative incidence function (CIF) for a failure of interest, which are separately specified in the logistic regression model and semiparametric regression model with time-varying and time-invariant effects. Based on two-stage method, we develop novel estimation equations using the inverse probability censoring weight techniques. The asymptotic properties of the estimators are rigorously studied and the plug-in variance estimators can be obtained for constructing interval estimators. We also propose a lack-of-fit test for assessing the adequacy of the proposed model and several tests for time-varying effects. The simulation studies and vascular access thrombosis data analysis are conducted to illustrate the proposed method.
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http://dx.doi.org/10.1002/sim.8711DOI Listing
November 2020

Propofol Improved Glucose Tolerance Associated with Increased FGF-21 and GLP-1 Production in Male Sprague-Dawley Rats.

Molecules 2020 Jul 15;25(14). Epub 2020 Jul 15.

Department of Medical Research, Taichung Veterans General Hospital, Taichung City 407, Taiwan.

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.
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http://dx.doi.org/10.3390/molecules25143229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397023PMC
July 2020

Quercetin protects against cerebral ischemia/reperfusion and oxygen glucose deprivation/reoxygenation neurotoxicity.

J Nutr Biochem 2020 09 30;83:108436. Epub 2020 May 30.

Department of Medical Research, Taichung Veterans General Hospital, Taichung City, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung City, Taiwan. Electronic address:

Beyond nutrition effect, quercetin is applied as a complement or an alternative for promoting human health and treating diseases. However, its complicated neuroprotective mechanisms have not yet been fully elucidated. This study provides evidence of an alternative target for quercetin, and sheds light on the mechanisms of its neuroprotection against cerebral ischemia/reperfusion (I/R) injury in Sprague-Dawley rats. Oral pretreatment using quercetin has alleviated cerebral I/R-induced neurological deficits, brain infarction, blood-brain barrier disruption, oxidative stress, TNF-α and IL-1β mRNA expression, along with apoptotic caspase 3 activity. The neuroprotective, anti-oxidative, anti-inflammatory, and anti-apoptotic effects of quercetin were replicated in rat hippocampal slice cultures and neuron/glia cultures which suffered from oxygen-glucose deprivation and reoxygenation (OGDR). Biochemical studies revealed a reduction of extracellular signal-regulated kinase (ERK) and Akt phosphorylation, along with an increase in protein tyrosine and serine/threonine phosphatase activity in cerebral I/R rat cortical tissues and OGDR hippocampal slice and neuron/glia cultures. Quercetin alleviated the changes in ERK/Akt phosphorylation and protein phosphatase activities. Inhibition of ERK or Akt alone was enough to cause apoptotic cell death and cytotoxicity in hippocampal slice cultures and neuron/glia cultures, while activators of ERK or Akt alleviated OGDR-induced cytotoxicity. Taken together, our results demonstrate that quercetin alleviated the increment of protein tyrosine and serine/threonine phosphatase activity, along with the reduction of ERK and Akt phosphorylation, which may play pivotal roles in the expansion of brain injury after cerebral I/R.
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http://dx.doi.org/10.1016/j.jnutbio.2020.108436DOI Listing
September 2020

Effects of β-Adrenergic Blockade on Metabolic and Inflammatory Responses in a Rat Model of Ischemic Stroke.

Cells 2020 06 1;9(6). Epub 2020 Jun 1.

Department of Medical Research, Taichung Veterans General Hospital, Taichung City 407, Taiwan.

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 β-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-while glucose augmented-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-α 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.
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http://dx.doi.org/10.3390/cells9061373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349353PMC
June 2020

β-Funaltrexamine Displayed Anti-inflammatory and Neuroprotective Effects in Cells and Rat Model of Stroke.

Int J Mol Sci 2020 May 29;21(11). Epub 2020 May 29.

Department of Medical Research, Taichung Veterans General Hospital, Taichung City 407, Taiwan.

Chronic treatment involving opioids exacerbates both the risk and severity of ischemic stroke. We have provided experimental evidence showing the anti-inflammatory and neuroprotective effects of the μ opioid receptor antagonist β-funaltrexamine for neurodegenerative diseases in rat neuron/glia cultures and a rat model of cerebral Ischemia/Reperfusion (I/R) injury. Independent of in vitro Lipopolysaccharide (LPS)/interferon (IFN-γ)-stimulated neuron/glia cultures and in vivo cerebral I/R injury in Sprague-Dawley rats, β-funaltrexamine downregulated neuroinflammation and ameliorated neuronal degeneration. Alterations in microglia polarization favoring the classical activation state occurred in LPS/IFN-γ-stimulated neuron/glia cultures and cerebral I/R-injured cortical brains. β-funaltrexamine shifted the polarization of microglia towards the anti-inflammatory phenotype, as evidenced by decreased nitric oxide, tumor necrosis factor-α, interleukin-1β, and prostaglandin E2, along with increased CD163 and arginase 1. Mechanistic studies showed that the suppression of microglia pro-inflammatory polarization by β-funaltrexamine was accompanied by the reduction of NF-κB, AP-1, cyclic AMP response element-binding protein, along with signal transducers and activators of transcription transcriptional activities and associated upstream activators. The effects of β-funaltrexamine are closely linked with its action on neuroinflammation by switching microglia polarization from pro-inflammatory towards anti-inflammatory phenotypes. These findings provide new insights into the anti-inflammatory and neuroprotective mechanisms of β-funaltrexamine in combating neurodegenerative diseases, such as stroke.
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http://dx.doi.org/10.3390/ijms21113866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313048PMC
May 2020

Use DN4-T questionnaire to rule out non-neuropathic pain.

J Chin Med Assoc 2020 05;83(5):510

Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan, ROC.

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http://dx.doi.org/10.1097/JCMA.0000000000000260DOI Listing
May 2020

Expression of Nik-related kinase in smooth muscle cells attenuates vascular inflammation and intimal hyperplasia.

Aging (Albany NY) 2020 04 24;12(8):7511-7533. Epub 2020 Apr 24.

Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan.

Inflammation of the vascular microenvironment modulates distinct types of vascular cells, and plays important roles in promoting atherosclerosis, stenosis/restenosis, and vascular-related diseases. Nik-related kinase (Nrk), a member of the Ste20-type kinase family, has been reported to be selectively expressed in embryonic skeletal muscle. However, whether Nrk is expressed in adult vascular smooth muscle, and if it influences intimal hyperplasia is unclear. Here, we found that Nrk is abundantly expressed in cultured vascular smooth muscle cells (VSMC) and mouse arterial intima. Treatment of mouse VSMCs with lipopolysaccharide (LPS) or platelet-derived growth factor significantly reduced Nrk expression. In addition, expression of Nrk was significantly reduced in regions of neointimal formation caused by guide-wire carotid artery injuries in mice, as well as in human atherosclerotic tissues, when compared to normal vessels. We identified that expression of matrix metalloproteinases (MMP3, MMP8 and MMP12) and inflammatory cytokines/chemokines (CCL6, CCL8, CCL11, CXCL1, CXCL3, CXCL5 and CXCL9) are synergistically induced by Nrk siRNA in LPS-treated mouse VSMCs. Moreover, we found that resveratrol significantly impaired LPS- and Nrk siRNA-induced expression of MMP3, CCL8, CCL11, CXCL3 and CXCL5. These results suggested that Nrk may play important roles in regulating pathological progression of atherosclerosis or neointimal- hyperplasia-related vascular diseases.
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http://dx.doi.org/10.18632/aging.103104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202544PMC
April 2020

Drug-coated balloon versus conventional balloon angioplasty of hemodialysis arteriovenous fistula or graft: A systematic review and meta-analysis of randomized controlled trials.

PLoS One 2020 14;15(4):e0231463. Epub 2020 Apr 14.

Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.

Background: Restenosis remains a significant problem in endovascular therapy for hemodialysis vascular access. Drug-coated balloon (DCB) angioplasty decreases restenosis in peripheral and coronary artery diseases. The aim of this systematic review and meta-analysis is to assess the patency outcomes following DCB angioplasty, as compared to conventional balloon (CB) angioplasty for the stenosis of hemodialysis vascular access.

Methods: A comprehensive search in the MEDLINE, EMBASE, and CENTRAL databases was conducted in order to identify eligible randomized controlled trials evaluating DCB angioplasty for hemodialysis vascular access dysfunction. The primary endpoint was the 6-month target lesion primary patency and the secondary endpoints were 12-month target lesion primary patency and procedure-related complications. Risk ratios (RR) were pooled and relevant subgroups were analyzed separately.

Results: Eleven randomized controlled trials comprised of 487 patients treated with DCB angioplasty and 489 patients treated with CB angioplasty were included. There were no significant differences in the target lesion primary patency at 6 months [RR, 0.75; 95% confidence interval (CI), 0.56, 1.01; p = 0.06] and at 12 months (RR 0.89; 95% CI, 0.79, 1.00; p = 0.06). The absence of benefit for the DCB group remained, even in the arteriovenous fistula subgroup or the subgroup of studies excluding central vein stenosis. The risk of procedure-related complication did not differ between the two groups (RR 1.00; 95% CI 0.98, 1.02; p = 0.95).

Conclusion: DCB angioplasty did not demonstrate significant patency benefit for the treatment of hemodialysis vascular access dysfunction. Wide variations in patency outcomes across studies were noted. Further studies focusing on specific types of access or lesions are warranted to clarify the value of DCB for hemodialysis vascular access. (PROSPERO Number CRD42019119938).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231463PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156061PMC
July 2020

Oral Charcoal Adsorbents Attenuate Neointima Formation of Arteriovenous Fistulas.

Toxins (Basel) 2020 04 8;12(4). Epub 2020 Apr 8.

Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.

Chronic kidney disease (CKD) accelerates the development of neointima formation at the anastomosis site of arteriovenous (AV) fistulas. Accumulation of certain uremic toxins has a deleterious effect on the cardiovascular system. The oral charcoal adsorbent, AST-120, reduces circulating and tissue uremic toxins, but its effect on neointima formation at an AV fistula is unknown. To understand the effect of CKD and AST-120 on neointima formation, we created AV fistulas (common carotid artery to the external jugular vein in an end-to-side anastomosis) in mice with and without CKD. AST-120 was administered in chow before and after AV fistula creation. Administration of AST-120 significantly decreased serum indoxyl sulfate levels in CKD mice. CKD mice had a larger neointima area than non-CKD mice, and administration of AST-120 in CKD mice attenuated neointima formation. Both smooth muscle cell and fibrin components were increased in CKD mice, and AST-120 decreased both. RNA expression of MMP-2, MMP-9, TNFα, and TGFβ was increased in neointima tissue of CKD mice, and AST-120 administration neutralized the expression. Our results provided in vivo evidence to support the role of uremic toxin-binding therapy on the prevention of neointima formation. Peri-operative AST-120 administration deserves further investigation as a potential therapy to improve AV fistula patency.
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http://dx.doi.org/10.3390/toxins12040237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232464PMC
April 2020

Aspirin Mitigated Tumor Growth in Obese Mice Involving Metabolic Inhibition.

Cells 2020 02 28;9(3). Epub 2020 Feb 28.

Department of Medical Research, Taichung Veterans General Hospital, Taichung City 407, Taiwan.

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.
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http://dx.doi.org/10.3390/cells9030569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140453PMC
February 2020

Endoplasmic Reticulum Stress Contributes to Indomethacin-Induced Glioma Apoptosis.

Int J Mol Sci 2020 Jan 15;21(2). Epub 2020 Jan 15.

Department of Medical Research, Taichung Veterans General Hospital, Taichung City 407, Taiwan.

The dormancy of cellular apoptotic machinery has been highlighted as a crucial factor in therapeutic resistance, recurrence, and poor prognosis in patients with malignancy, such as malignant glioma. Increasing evidence indicates that nonsteroidal anti-inflammatory drugs (NSAIDs) confer chemopreventive effects, and indomethacin has been shown to have a novel chemotherapeutic application targeting glioma cells. To extend these findings, herein, we studied the underlying mechanisms of apoptosis activation caused by indomethacin in human H4 and U87 glioma cells. We found that the glioma cell-killing effects of indomethacin involved both death receptor- and mitochondria-mediated apoptotic cascades. Indomethacin-induced glioma cell apoptosis was accompanied by a series of biochemical changes, including reactive oxygen species generation, endoplasmic reticulum (ER) stress, apoptosis signal-regulating kinase-1 (Ask1) activation, p38 hyperphosphorylation, protein phosphatase 2A (PP2A) activation, Akt dephosphorylation, Mcl-1 and FLICE-inhibiting protein (FLIP) downregulation, Bax mitochondrial distribution, and caspases 3/caspase 8/caspase 9 activation. Data on pharmacological inhibition related to oxidative stress, ER stress, free Ca, and p38 revealed that the axis of oxidative stress/ER stress/Ask1/p38/PP2A/Akt comprised an apoptotic cascade leading to Mcl-1/FLIP downregulation and glioma apoptosis. Since indomethacin is an emerging choice in chemotherapy and its antineoplastic effects have been demonstrated in glioma tumor-bearing models, the findings further strengthen the argument for turning on the aforementioned axis in order to activate the apoptotic machinery of glioma cells.
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http://dx.doi.org/10.3390/ijms21020557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013513PMC
January 2020

Arterial compression by an adjacent venous stent graft in a patient undergoing dialysis.

J Vasc Access 2020 Nov 11;21(6):1042-1044. Epub 2019 Dec 11.

Cardiovascular Center, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu.

Background: Stent graft is effective for management of balloon-angioplasty-related complications in hemodialysis access. These complications include post-angioplasty venous rupture, dissection/recoil, and acute formation of pseudoaneurysm.

Case Report: We report a stent-graft complication that caused immediate acute arterial insufficiency by external compression. An 84-year-old woman presented with acute arteriovenous graft thrombosis. During percutaneous balloon thrombectomy, a stent graft was placed because of persistent recoil and mural thrombus, but the flow into the arteriovenous graft immediately ceased. External compression of the brachial artery was observed. A nitinol self-expandable stent was deployed in the brachial artery to oppose the external compression. The flow in the arteriovenous graft was recovered.

Conclusion: This case demonstrates the possibility of arterial compression by an adjacent venous stent graft, especially in a patient with a thin habitus and a brachial-brachial arteriovenous graft. Detailed identification of the outflow vein anatomy before stent implantation is mandatory to avoid such a complication.
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http://dx.doi.org/10.1177/1129729819888419DOI Listing
November 2020

Left stellate ganglion block, a rescue treatment for ventricular arrhythmia refractory to radiofrequency catheter ablation: A care-compliant case report.

Medicine (Baltimore) 2019 Nov;98(44):e17790

Taichung Veterans General Hospital, Department of Anesthesiology, 1650 Taiwan Boulevard Sect. 4, Taichung 40705, Taiwan ROC.

Rationale: Stellate Ganglion Block (SGB) provides a blockade of sympathetic signals from the sympathetic chain and appears to be a promising method of controlling refractory ventricular arrhythmias, but there are scanty data in the literature.

Patient Concerns: Herein, we describe a 59-year-old male patient with a history of non-ischemic cardiomyopathy and suffering from frequent VT episodes, who received ICD implantation and regular amiodarone medication control.

Diagnoses: Monomorphic VT refractory to standard medication control and focal extensive catheter ablation.

Interventions: Left Stellate Ganglion Block (LSGB) was performed under ultrasound-assisted injection at the C6 level using a 10 ml solution of 0.4% lidocaine and 0.5% bupivacaine.

Outcomes: In our case, refractory VT subsided and sinus rhythm was retained immediately after LSGB. There were no VT episodes for at least 3 hours during the inter-hospital transfer, which did not involve any specific complications.

Lessons: LSGB may provide effective VT control and play an important role in rescue and bridge therapy before catheter ablation.
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http://dx.doi.org/10.1097/MD.0000000000017790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946516PMC
November 2019

Dimethylarginine Dimethylaminohydrolase 1 Polymorphisms and Venous Intimal Hyperplasia in Hemodialysis Patients.

Am J Nephrol 2019 22;50(6):454-464. Epub 2019 Oct 22.

Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan,

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.
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http://dx.doi.org/10.1159/000503949DOI Listing
September 2020

A randomized controlled trial of drug-coated balloon angioplasty in venous anastomotic stenosis of dialysis arteriovenous grafts.

J Vasc Surg 2020 06 11;71(6):1994-2003. Epub 2019 Oct 11.

College of Medicine, National Taiwan University, Taipei, Taiwan; Institute of Biomedical Engineering, National Tsing-Hua University, Hsinchu, Taiwan; Cardiovascular Center, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan; Institute of Cellular and System Medicine, National Health Research Institute, Miaoli, Taiwan. Electronic address:

Objective: Paclitaxel-coated balloons are used to reduce neointimal hyperplasia in native arteriovenous (AV) fistulas. However, no study specifically evaluated their effect on venous anastomotic stenosis of dialysis grafts. We aimed to compare the efficacy of angioplasty with drug-coated balloons (DCBs) and angioplasty with conventional balloons (CBs) for venous anastomotic stenosis in dysfunctional AV grafts.

Methods: In this investigator-initiated, single-center, single-blinded, prospective randomized controlled trial, we randomly assigned 44 patients who had venous anastomotic stenosis to undergo angioplasty with DCBs (n = 22) or CBs (n = 22) from July 2015 to August 2018. Access function was observed per the hemodialysis center's protocols; ancillary angiographic follow-up was performed every 2 months for 1 year after the interventions. The primary end point was target lesion primary patency at 6 months. Secondary outcomes included anatomic and clinical success after angioplasty, circuit primary patency at 6 months and 1 year, and target lesion primary patency at 1 year.

Results: At 6 months, target lesion primary patency in the DCB group was significantly greater than that in the CB group (41% vs 9%; hazard ratio [HR], 0.393; 95% confidence interval [CI], 0.194-0.795; P = .006), as was the primary patency of the entire access circuit (36% vs 9%; HR, 0.436; 95% CI, 0.218-0.870; P = .013). At 1 year, the target lesion primary patency in the DCB group remained greater than that in the CB group (23% vs 9%; HR, 0.477; 95% CI, 0.243-0.933; P = .019) but not the primary patency of the access circuit (14% vs 9%; HR, 0.552; 95% CI, 0.288-1.059; P = .056). No difference in anatomic or clinical success was observed; no major complications were noted.

Conclusions: Angioplasty with DCBs showed a modest improvement in primary patency of venous anastomotic stenosis and all dialysis AV grafts at 6 months. The short-term benefit was not durable to 1 year, and reinterventions were eventually needed.
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http://dx.doi.org/10.1016/j.jvs.2019.07.090DOI Listing
June 2020

The impact of door-to-electrocardiogram time on door-to-balloon time after achieving the guideline-recommended target rate.

PLoS One 2019 9;14(9):e0222019. Epub 2019 Sep 9.

College of Medicine, National Taiwan University, Taipei, Taiwan.

Background: Little is known about the components and contributing factors of door-to-balloon time after implementation of Door-to-Balloon Alliance quality-improving (QI) strategies, including the impact of door-to-ECG time on door-to-balloon time.

Objective: We investigated whether modification of emergency department (ED) triage processes could improve door-to-ECG and door-to-balloon times after implementation of QI strategies.

Methods: This was a retrospective before-and-after study of a prospectively collected database. From June 2014 to October 2014, interventions were implemented in our ED, including a protocol-driven ECG initiation and moving an ECG station and technician to the triage area. The primary outcome was the percentage of patients with ST-elevation myocardial infarction (STEMI) who received ECG within 10 min of arrival; the secondary outcome was the percentage of patients with door-to-balloon times of <90 min from arrival. Patients from the year pre- and post-QI initiative were defined as the control and intervention groups, respectively.

Results: Enrollment comprised 214 patients with STEMI: 109 before the intervention and 105 after the intervention. We analyzed the components of the door-to-balloon process and found the door-to-ECG process was the most critical interval of delay (20.8%). Unrecognized symptoms were the most common cause of delay in the door-to-ECG process resulting in a significant impact on the door-to-balloon time. The intervention group had a higher percentage of patients with door-to-ECG times <10 min than did the control group (93.3% vs. 79.8%, p = 0.005), with a corresponding improvement in door-to-balloon times <90 min (91.1% vs. 76.2%, p = 0.007). In subgroup analysis, the intervention benefits occurred only in non-transferred or walk-in patients. After adjustment for possible co-variates, the QI interventions remained a significant contributing factor for achieving the door-to-ECG and door-to-balloon targets.

Conclusions: The modification of ED triage processes through implementation of QI strategies are effective in achieving better door-to-ECG times and thus, achieving door-to-balloon times <90 min. In patients presenting with ambiguous symptoms, improved door-to ECG target achievement rates, through a protocol-driven and multidisciplinary approach allows for earlier identification of STEMI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222019PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733447PMC
March 2020