Mitochondrial reactive oxygen species (mROS) that are overproduced by mitochondrial dysfunction are linked to pathological conditions including sensory abnormalities. Here, we explored whether mROS overproduction induces itch through transient receptor potential canonical 3 (TRPC3), which is sensitive to ROS. Intradermal injection of antimycin A (AA), a selective inhibitor of mitochondrial electron transport chain complex III for mROS overproduction, produced robust scratching behavior in naïve mice, which was suppressed by MitoTEMPO, a mitochondria-selective ROS scavenger, and Pyr10, a TRPC3-specific blocker, but not by blockers of TRPA1 or TRPV1. AA activated subsets of trigeminal ganglion neurons and also induced inward currents, which were blocked by MitoTEMPO and Pyr10. Besides, dry skin-induced chronic scratching was relieved by MitoTEMPO and Pyr10, and also by resveratrol, an antioxidant. Taken together, our results suggest that mROS elicit itch through TRPC3, which may underlie chronic itch, representing a potential therapeutic target for chronic itch.
Animals ; Antioxidants/pharmacology* ; Mice ; Mitochondria ; Pruritus/chemically induced* ; Reactive Oxygen Species/metabolism* ; TRPA1 Cation Channel

Background: Obesity, the prevalence of which is increasing due to the lack of exercise and increased consumption of Westernized diets, induces various complications, including ophthalmic diseases. For example, obesity is involved in the onset of cataracts. Methods: To clarify the effects and mechanisms of midodrine, an α1-adrenergic receptor agonist, in cataracts induced by obesity, we conducted various analytic experiments in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a rat model of obesity. Results: Midodrine prevented cataract occurrence and improved lens clearance in OLETF rats. In the lenses of OLETF rats treated with midodrine, we observed lower levels of aldose reductase, tumor necrosis factor-α, and sorbitol, but higher levels of hexokinase, 5’-adenosine monophosphate-activated protein kinase-alpha, adenosine 5´-triphosphate, peroxisome proliferator-activated receptordelta, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, superoxide dismutase, and catalase. Conclusion The ameliorating effects of midodrine on cataracts in the OLETF obesity rat model are exerted via the following three mechanisms: direct inhibition of the biosynthesis of sorbitol, which causes cataracts; reduction of reactive oxygen species and inflammation; and (3) stimulation of normal aerobic glycolysis.

Purpose: Since diabetes and hypertension frequently occur together, it is thought that these conditions may have a common pathogenesis. This study was designed to evaluate the anti-diabetic function of the anti-hypertensive drug fimasartan on C2C12 mouse skeletal muscle and HepG2 human liver cells in a high glucose state. Materials and Methods: The anti-diabetic effects and mechanism of fimasartan were identified using Western blot, glucose uptake tests, oxygen consumption rate (OCR) analysis, adenosine 5'-triphosphate (ATP) enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining for diabetic biomarkers in C2C12 cells. Protein biomarkers for glycogenolysis and glycogenesis were evaluated by Western blotting and ELISA in HepG2 cells. Results: The protein levels of phosphorylated 5' adenosine monophosphate-activated protein kinase (p-AMPK), p-AKT, insulin receptor substrate-1 (IRS-1), and glucose transporter type 4 (Glut4) were elevated in C2C12 cells treated with fimasartan. These increases were reversed by peroxisome proliferator-activated receptor delta (PPARδ) antagonist. ATP, OCR, and glucose uptake were increased in cells treated with 200 μM fimasartan. Protein levels of glycogen phosphorylase, glucose synthase, phosphorylated glycogen synthase, and glycogen synthase kinase-3 (GSK-3) were decreased in HepG2 cells treated with fimasartan. However, these effects were reversed following the addition of the PPARδ antagonist GSK0660. Conclusion In conclusion, fimasartan ameliorates deteriorations in glucose metabolism as a result of a high glucose state by regulating PPARδ in skeletal muscle and liver cells.

Background and Objectives: Cavotricuspid isthmus (CTI) block is easily achieved, and prophylactic ablation can be performed during atrial fibrillation (AF) ablation. However, the previous study was too small and short-term to clarify the efficacy of this block. Methods: Patients who underwent catheter ablation for paroxysmal AF were enrolled, and patients who had previous or induced atrial flutter (AFL) were excluded. We randomly assigned 366 patients to pulmonary vein isolation (PVI) only and prophylactic CTI ablation (PVI vs. PVI+CTI). Results: There was no significant difference in procedure time between the two groups because most CTI blocks were performed during the waiting time after the PVI (176.8±72.6 minutes in PVI vs. 174.2±76.5 minutes in PVI+CTI, p=0.75). All patients were followed up for at least 18 months, and the median follow-up was 3.4 years. The recurrence rate of AF or AFL was not different in the 2 groups (25.7% in PVI vs. 25.7% in PVI+CTI, p=0.92). The recurrence rate of any AFL was not significantly different in the 2 groups (3.3% in PVI vs. 1.6% in PVI+CTI, p=0.31). The recurrence rate of typical AFL also was not different (0.5% in PVI vs. 0.5% in PVI+CTI, p=0.99). Conclusions In this large and long-term follow-up study, prophylactic CTI ablation had no benefit in patients with paroxysmal AF without typical AFL.

Background and Objectives: Cavotricuspid isthmus (CTI) block is easily achieved, and prophylactic ablation can be performed during atrial fibrillation (AF) ablation. However, the previous study was too small and short-term to clarify the efficacy of this block. Methods: Patients who underwent catheter ablation for paroxysmal AF were enrolled, and patients who had previous or induced atrial flutter (AFL) were excluded. We randomly assigned 366 patients to pulmonary vein isolation (PVI) only and prophylactic CTI ablation (PVI vs. PVI+CTI). Results: There was no significant difference in procedure time between the two groups because most CTI blocks were performed during the waiting time after the PVI (176.8±72.6 minutes in PVI vs. 174.2±76.5 minutes in PVI+CTI, p=0.75). All patients were followed up for at least 18 months, and the median follow-up was 3.4 years. The recurrence rate of AF or AFL was not different in the 2 groups (25.7% in PVI vs. 25.7% in PVI+CTI, p=0.92). The recurrence rate of any AFL was not significantly different in the 2 groups (3.3% in PVI vs. 1.6% in PVI+CTI, p=0.31). The recurrence rate of typical AFL also was not different (0.5% in PVI vs. 0.5% in PVI+CTI, p=0.99). Conclusions In this large and long-term follow-up study, prophylactic CTI ablation had no benefit in patients with paroxysmal AF without typical AFL.

Background and Objectives: The efficacy of radiofrequency catheter ablation (RFCA) in atrial fibrillation (AF) is well established. The standard approach to RFCA in AF is pulmonary vein isolation (PVI). However, a large proportion of patients experiences recurrence of atrial tachyarrhythmia. The purpose of this study is to find out whether the AI model can assess AF recurrence in patients who underwent PVI. Materials and methods: This study was a retrospective cohort study that enrolled consecutive patients who under‑ went catheter ablation for symptomatic, drug-refractory AF and PVI. We developed an AI algorithm to predict recur‑ rence of AF after PVI using patient demographics and three-dimensional (3D) reconstructed left atrium (LA) images. Results: We included 527 consecutive patients in the study. The overall mean LA diameter was 42.0 ± 6.8 mm, and the mean LA volume calculated using 3D reconstructed images was 151.1 ± 46.7 ml. During the follow-up period, atrial tachyarrhythmia recurred in 158 patients. The area under the curve (AUC) of the AI model based on a convolu‑ tional neural network (including 3D reconstruction images) was 0.61 (95% confidence interval [CI] 0.53–0.74) using the test dataset. The total test accuracy was 66.3% (57.0–75.6), and the sensitivity was 53.3% (34.8–71.9). The specificity was 73.2% (51.8–75.0), and the F1 score was 52.5% 34.5–66.7). Conclusion In this study, we developed an AI algorithm to predict recurrence of AF after catheter ablation of PVI using individual reconstructed LA images. This AI model was unable to predict recurrence of AF overwhelmingly;therefore, further large-scale study is needed.

Purpose: The introduction of immune checkpoint inhibitors represents a major advance in the treatment of lung cancer, allowing sustained recovery in a significant proportion of patients. Nivolumab is a monoclonal anti–programmed death cell protein 1 antibody licensed for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy. In this study, we describe the demographic and clinical outcomes of patients with advanced NSCLC treated with nivolumab in the Korean expanded access program. Materials and Methods: Previously treated patients with advanced non-squamous and squamous NSCLC patients received nivolumab at 3 mg/kg every 2 weeks up to 36 months. Efficacy data including investigator-assessed tumor response, progression data, survival, and safety data were collected. Results: Two hundred ninety-nine patients were treated across 36 Korean centers. The objective response rate and disease control rate were 18% and 49%, respectively; the median progression-free survival was 2.1 months (95% confidence interval [CI], 1.87 to 3.45), and the overall survival (OS) was 13.2 months (95% CI, 10.6 to 18.9). Patients with smoking history and patients who experienced immune-related adverse events showed a prolonged OS. Cox regression analysis identified smoking history, presence of immune-related adverse events as positive factors associated with OS, while liver metastasis was a negative factor associated with OS. The safety profile was generally comparable to previously reported data. Conclusion This real-world analysis supports the use of nivolumab for pretreated NSCLC patients, including those with an older age.

BACKGROUND AND OBJECTIVES: The aim of this study was to investigate the effectiveness and selected adverse events of radiofrequency catheter ablation in patients treated for drug-refractory atrial fibrillation (AF) using claims data provided by the Health Insurance Review and Assessment Service, which covers all ablation procedures conducted in South Korea. SUBJECTS AND METHODS: The study population included patients who underwent catheter ablation for AF between January 2011 and December 2013. A total of 3,850 patients without a previous history of catheter ablation procedure were enrolled. We analyzed 2-year effectiveness of the index ablation. Any redo ablation, electrical cardioversion, or use of antiarrhythmic drug beyond the blanking period of 3 months was considered a failure of index ablation. RESULTS: Overall recurrence rate following AF ablation was 61.1%. The recurrence rate was lower in patients under 65 years old than in those over 65 years old (hazard ratio [HR] 0.89; 95% confidence interval [CI], 0.81 to 0.97, P=0.009). Repeat ablation was more frequent in men (HR 1.56; 95% CI, 1.20 to 2.04; P=0.001) and patients under 65 years old (HR 1.79; 95% CI, 1.34 to 2.38; P < 0.001). Electric cardioversion was more frequent in men (HR 1.35; 95% CI, 1.06 to 1.72; P=0.014) than in women. The overall rate of stroke, blood transfusion, significant pericardial complication, and cardiopulmonary resuscitation was 0.5%, 4.8%, 2.7%, and 0.2%, respectively. CONCLUSIONS: In the present study, old age was associated with treatment failure of catheter ablation for drug-refractory AF in the Korean population. Overall recurrence did not vary with respect to sex.
Atrial Fibrillation ; Blood Transfusion ; Cardiopulmonary Resuscitation ; Catheter Ablation ; Catheters ; Electric Countershock ; Female ; Hemorrhage ; Humans ; Insurance, Health ; Korea ; Male ; Pericardiocentesis ; Recurrence ; Stroke ; Treatment Failure

BACKGROUND AND OBJECTIVES: Electroanatomical mapping using a three-dimensional (3D) system has high accuracy and improves the results of the ablation of outflow tract (OT) premature ventricular contraction (PVC) or ventricular tachycardia (VT) but imposes a considerable economic burden. Here, we compared detailed diagnostic catheterization and 3D mapping system for the ablation of OT PVC/VT. MATERIALS AND METHODS: Between June 2012 and February 2017, patients with symptomatic OT PVC/VT underwent radiofrequency ablation. Group 1 underwent detailed diagnostic catheterization (using circular and linear multielectrodes) without a 3D mapping system, while group 2 underwent diagnostic catheterization using a conventional 3D mapping system. Procedural success of PVC reduction, remaining symptoms, need for post-operative medications, and procedural time were evaluated. RESULTS: Ninety-eight OT PVC/VT cases were consecutively enrolled. The mean follow-up period was 17.7±14.5 months. Neither acute success rate (95% vs. 82%, p=0.06) nor a PVC reduction > 80% (84% vs. 87%, p=0.74) differed significantly between the two groups. The recurrence rates of PVC-related symptoms were similar (12% vs. 7%, p=0.06) between the groups, but the medication requirement for symptomatic PVC differed (12% vs. 29%, p < 0.01). The total procedure time of group 1 was shorter than that of group 2 (132±42 min vs. 157±47 min, p=0.01) and fluoroscopy time (24±15 min vs. 38±22 min, p < 0.01) and ablation time (528±538 sec vs. 899±598 sec, p < 0.01) were also significantly shortened. CONCLUSION: Detailed electrode catheter positioning is a safe and cost-effective method for the ablation of OT PVC/VT.
Arrhythmias, Cardiac* ; Catheter Ablation ; Catheterization ; Catheters* ; Electrodes* ; Fluoroscopy ; Follow-Up Studies ; Humans ; Methods ; Recurrence ; Tachycardia, Ventricular ; Ventricular Premature Complexes

BACKGROUND AND OBJECTIVES: In cases of radiofrequency catheter ablation (RFCA) for patients with atrioventricular nodal re-entrant tachycardia (AVNRT), complete elimination of slow pathway is not always achievable. Furthermore, in situations of the so-called modified slow pathway, the underlying mechanism of tachycardia elimination remains unclear. SUBJECTS AND METHODS: Patients who underwent RFCA for AVNRT, and showed persistence of dual atrioventricular nodal physiology but no induction of AVNRT after ablation were enrolled. We measured electrophysiologic parameters before and after the ablation procedure. RESULTS: The study subjects included 31 patients (39% men; mean age 43±19 years). The RR interval, Wenckebach cycle length of AV node, slow pathway effective refractory period, maximal AH interval of fast pathway and slow pathway showed no significant changes before and after ablation. However, fast pathway effective refractory period (360±67 vs. 304±55, p<0.001) and differences between slow pathway effective refractory period and fast pathway effective refractory period (90±49 vs. 66±35, p=0.009) were decreased after slow pathway ablation. CONCLUSION: We suggest a possible relationship between the mechanism of tachycardia elimination in AVNRT and an alteration of the re-entrant circuit by removal of the atrial tissue in Koch's triangle. This may be a critical component of providing the excitable gap for the maintenance of tachycardia rather than the electrical damage of slow pathway itself.
Atrioventricular Node* ; Catheter Ablation ; Humans ; Male ; Physiology* ; Tachycardia*