Edoxaban-based long-term antithrombotic therapy in patients with atrial fibrillation and stable coronary disease: Rationale and design of the randomized EPIC-CAD trial.

BACKGROUND: Anticoagulants are the standard therapy for patients with atrial fibrillation (AF) and antiplatelet therapy for those with coronary artery disease (CAD). However, compelling clinical evidence is still lacking regarding the long-term maintenance strategy with the combination of anticoagulant and antiplatelet drugs in patients with AF and stable CAD. DESIGN: The EPIC-CAD trial is an investigator-initiated, multicenter, open-label randomized trial comparing the safety and efficacy of 2 antithrombotic strategies in patients with high-risk AF (CHA2DS2-VASc score ≥ 2 points) and stable CAD (≥6 months after revascularization for stable angina or ≥12 months for acute coronary syndrome; or medical therapy alone). Patients (approximately N = 1,038) will be randomly assigned at a 1:1 ratio to (1) monotherapy with edoxaban (a non-vitamin K antagonist oral anticoagulant) or (2) combination therapy with edoxaban plus a single antiplatelet agent. The primary endpoint is the net composite outcome of death from any cause, stroke, systemic embolism, myocardial infarction, unplanned revascularization, and major or clinically relevant nonmajor bleeding at 1 year after randomization. RESULTS: As of December 2021, approximately 901 patients had been randomly enrolled over 2 years at 18 major cardiac centers across South Korea. The completed enrollment is expected at the mid-term of 2022, and the primary results will be available by 2023. CONCLUSIONS: EPIC-CAD is a large-scale, multicenter, pragmatic design trial, which will provide valuable clinical insight into edoxaban-based long-term antithrombotic therapy in patients with high-risk AF and stable CAD.

Bleeding risk in patients with atrial fibrillation treated with combined anti-platelet and non-vitamin K antagonist oral anticoagulant therapy.

BACKGROUND: The use of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with non-valvular atrial fibrillation (AF) has been increasing. Accordingly, the combined use of antiplatelet agents (APT) and NOAC therapy is commonly encountered in clinical practice. The purpose of this study was to compare the clinical outcomes between combination therapy (NOAC and APT) vs. monotherapy (NOAC only) in patients with AF. METHODS: We retrospectively analyzed patients who were prescribed NOACs between January 2012 and December 2016. The primary outcome was major bleeding and any bleeding events, and the secondary outcomes were stroke/systemic embolic (SE) events and major adverse cardiac events (MACE). RESULTS: Of the 1068 participants, there were 264 (24.7%) patients in the combination therapy group. The prevalence of diabetes (p = 0.017) and history of stroke and transient ischemic attacks (p < 0.001) was higher in the combination group than in the monotherapy group. During the mean 14.6 ± 9.8 months of follow-up, the incidence of any bleeding was significantly higher in the combination therapy group than in the monotherapy group (p < 0.001). The rate of major bleeding, stroke/SE, and MACE between the two groups was similar. The rate of under-dosage NOAC prescriptions was higher in the combination therapy group than in the monotherapy group (p = 0.024). CONCLUSIONS: The combination therapy group had higher incidences of any bleeding events compared to the monotherapy in patients with appropriate dosing. However, there was no difference in stroke/SE, and MACE. The bleeding risk in AF patients taking the combination of NOACs and APT should be carefully evaluated.

Effects of Sodium-Glucose Cotransporter-2 Inhibitors and Thiazolidinedione on New-Onset Atrial Fibrillation Risk to Patients with Type 2 Diabetes.

Background and Objectives: Type 2 diabetes (T2D) is an independent risk factor for the development of atrial fibrillation (AF). Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have recently been shown to decrease the incidence of AF through several mechanisms, including the reduction of atrial dilatation via diuresis and the lowering of body weight. In observational studies of diabetic patients, the use of thiazolidinedione (TZD) was found to have a protective effect on new-onset AF. In this study, we aimed to compare the effect of SGLT-2i and TZD on the risk of AF in patients with T2D. Methods: We enrolled 69,122 patients newly prescribed SGLT-2i and 94,262 patients prescribed TZD from January 2014 to December 2018, using the Korean National Health Insurance Service database. We compared new-onset AF events (hospitalizations and outpatient events) in SGLT-2i and TZD groups after having taken medication for greater than 90 days. Results: During a mean follow-up of 1.8 years, 397 (0.72%) new-onset AF events occurred in the SGLT-2i group and 432 (0.79%) events in the TZD group following propensity score matching (each group n = 54,993). The hazard ratio (HR) of AF was 0.918 (95% confidence interval: 0.783-1.076, p = 0.29) in SGLT-2i-treated patients compared with TZD-treated patients. Conclusions: In this study, the risk of new-onset AF is comparable in patients treated with SGLT-2i and TZD in T2D. Either SGLT-2i or TZD would be a reasonable choice for T2D patients who are at risk for AF.

Social distancing, trust and post-COVID-19 recovery.

With the tourism and hospitality sector reopening post-lockdown of COVID-19, the recovery of customers' purchase intentions is essential to reboot the sector. This study aims to examine the relationship between social distancing measures and purchase intentions in the UK's restaurant and hotel sectors using a propensity score weighting experimental design method. The findings suggest that the impact of social distancing measures on purchase intentions is mediated by the trust in the targeted restaurant and hotel. Risk tolerance significantly moderates the influence of social distancing measures on trust; (non-) cash promotions have an insignificant impact on purchase intentions. The introduction of the propensity score weighting scheme addresses the endogeneity caused by the sampling bias in non-probability sampling experiment studies.

Complications of Cardiac Perforation and Lead Dislodgement with an MRI-Conditional Pacing Lead: a Korean Multi-Center Experience.

Medtronic CapSureFix MRI 5086 pacing lead (5086; Medtronic, Inc., Minneapolis, MN, USA) has been reported to be associated with increased cardiac perforation and lead dislodgement. This study aimed to compare the incidence of cardiac perforation and lead dislodgement within 30 days after pacemaker implantation between 5086 MRI lead and previous Medtronic CapSureFix Novus 5076 non-MRI pacing lead. This was a nationwide, multicenter retrospective study in which we compared the incidence of adverse events between 277 patients implanted with 5086 lead and 205 patients implanted with 5076 lead between March 2009 and September 2014. Cardiac perforation within 30 days of pacemaker implantation occurred in 4 patients (1.4%) with the 5086 lead and in no patient with the 5076 lead (P = 0.084). Lead dislodgement occurred in 8 patients (2.9%) with the 5086 lead and in 5 patients (2.4%) with the 5076 lead (P = 0.764). On multivariate logistic regression analysis, age was significantly associated with cardiac perforation. Congestive heart failure and implantation of right atrial (RA) lead at RA free wall or septum were significant factors for the incidence of lead dislodgement and lead revision. The incidence of cardiac perforation and lead dislodgement were not statistically different between the patients with 5086 lead and the patients with 5076 lead. However, careful attention for cardiac perforation may be needed when using the 5086 MRI lead, especially in elderly patients.

Admission B-type natriuretic peptide levels are associated with in-hospital cardiac events in patients with intracranial hemorrhage.

BACKGROUND: Intracranial hemorrhage (ICH) is often associated with cardiac events. Twelve-lead electrocardiography (ECG) and transthoracic echocardiography are essential diagnostic tools for preoperative risk assessment. B-type natriuretic peptide (BNP) is a well-known predictor of cardiac outcome in various clinical settings. This study examined whether BNP levels on admission are associated with in-hospital cardiac events among ICH patients. METHOD: This prospective study enrolled 77 ICH patients who were admitted to this hospital for emergency neurosurgery. On admission, BNP levels, 12-lead ECG and transthoracic echocardiography were carried out for all patients. These patients were divided into two groups: Group I included 19 patients (10 men and 9 women) having 24 in-hospital cardiac events (mean age of 57 ± 15 years); Group II included 57 patients (29 men, mean age of 71 ± 11 years) without cardiac events. RESULTS: Admission BNP levels of Group I patients were significantly higher than those of Group II patients (683.8 ± 1,043.8 pg/ml vs 168.5 ± 173.5 pg/ml, p = 0.001). In multivariate analysis, BNP levels and T-wave inversion are independent predictors of in-hospital cardiac events. A cutoff value of BNP levels (156.6 pg/ml) predicted in-hospital cardiac events in ICH patients with 80 % sensitivity and 66 % specificity. CONCLUSIONS: Serum BNP levels and electrocardiographic T-wave inversion on admission are independent predictors of in-hospital cardiac events in patients with ICH who undergo emergency neurosurgery.

Left Atrium Volume Measured with Multislice Computed Tomography as a Prognostic Predictor for Atrial Fibrillation Catheter Ablation Outcomes.

Background: Current guidelines consider atrial fibrillation (AF) type as the prognostic factor for a recommendation of catheter ablation. We aimed to determine whether LA and LA appendage (LAA) volumes measured using multislice computed tomography (MSCT) were related to long-term outcomes in AF following radiofrequency catheter ablation (RFCA). Methods: We evaluated 152 consecutive patients with drug-refractory AF (median age, 55.8 ± 9.6 years), including 110 male patients, who underwent RFCA in a single center. All patients underwent MSCT imaging for anatomical assessment. The endpoint of this study was documented AF recurrence after RFCA. Results: The overall procedure success rate was 77.6% (n = 118) during a mean follow-up period of 12.6 months. The LA volume was significantly larger for those who experienced AF recurrence after RFCA than for the patients without recurrent AF after the procedure (153.8 ± 29.9 mL vs. 139.2 ± 34.1 mL, p = 0.025). However, LAA volumes were nearly equivalent between the patients with and without AF recurrence after RFCA (16.2 ± 6.3 mL and 14.7 ± 6.5 mL, respectively; p = 0.235). LA volume ≥ 153.2 mL was the optimal cutoff value for estimating AF recurrence after RFCA, with 94% sensitivity and 66% specificity. LA volume remained an independent predictor of both AF recurrence and permanent AF. Conclusions: LA volume as assessed by MSCT might be helpful for identifying patients likely to achieve successful AF ablation. LA volume ≥ 153.2 mL, but not LAA volume, showed good accuracy in predicting AF recurrence after RFCA.

Case Report: Comprehensive evaluation of ECG phenotypes and genotypes in a family with Brugada syndrome carrying SCN5A-R376H.

Background: Brugada syndrome (BrS) is a channelopathy that can lead to sudden cardiac death in the absence of structural heart disease. Patients with BrS can be asymptomatic or present with symptoms secondary to polymorphic ventricular tachycardia or ventricular fibrillation. Even though BrS can exhibit autosomal dominant inheritance, it is not easy to identify the phenotype and genotype in a family thoroughly. Case: We report the case of a 20-year-old man with variants in SCN5A and RyR2 genes who was resuscitated from sudden cardiac death during sleep due to a ventricular fibrillation. The patient did not have underlying diseases. The routine laboratory results, imaging study, coronary angiogram, and echocardiogram (ECG) were normal. A type 1 BrS pattern was identified in one resting ECG. Furthermore, prominent J wave accentuation with PR interval prolongation was identified during therapeutic hypothermia. Therefore, we were easily able to diagnose BrS. For secondary prevention, the patient underwent implantable cardioverter defibrillator implantation. Before discharge, a genetic study was performed using next-generation sequencing. Genotyping was performed in the first-degree relatives, and ECG evaluations of almost all maternal and paternal family members were conducted. The proband and his mother showed SCN5A-R376H and RyR2-D4038Y variants. However, his mother did not show the BrS phenotype on an ECG. One maternal aunt and uncle showed BrS phenotypes. Conclusion: Genetics alone cannotdiagnose BrS. However, genetics could supply evidence or direction for evaluating ECG phenotypes in family groups. This case report shows how family evaluation using ECGs along with a genetic study can be used in BrS diagnosis.

Modified application of SAMe-TT2R2 scoring system in Asian patients with atrial fibrillation for the selection of oral anticoagulants.

BACKGROUND/AIMS: The SAMe-TT2R2 score is used for assessing anticoagulation control (AC) quality with warfarin. However, it is hard to apply SAMe-TT2R2 score in Asian patients with atrial fibrillation (AF), because it has not been proven in those populations. This study aimed to validate the SAMe-TT2R2 score in Asian patients with AF and suggest a modified SAMe- TT2R2 score for this population. METHODS: We analyzed 710 Korean patients with AF who were using warfarin. The AC quality was assessed as the mean time in therapeutic range (TTR). Each component of SAMe-TT2R2 score was evaluated for the relationship with AC. Further clinical factors that predict AC were analyzed. Identified factors were re-assorted and constructed as SA2Me-TTR scoring system. RESULTS: Of the components of the SAMe-TT2R2 score, female, age, and rhythm control were associated with AC. Heart failure and renal insufficiency were newly identified factors associated with AC. The modified SA2Me-TTR score was reconstructed with the relevant risk factors (S, female gender, 1 point; A, age < 60 yr, 2 points; Me, medical history of heart failure, 1 point; T, treatment for rhythm control, 1 point; T, history of stroke or transient ischemic attack, 1 point; R, renal insufficiency, 1 point). The modified SA2Me-TTR score demonstrated an excellent relationship with the grading of AC. The modified SA2Me-TTR score ≤ 1 identified patients with good AC (hazard ratio 2.46, 95% CI 1.75-3.47). CONCLUSION: The modified SA2Me-TTR score was useful for guiding oral anticoagulants selection in Asian patients with AF.

Evaluation of ventricular pacing suppression algorithms in dual chamber pacemaker: Results of "LEADER" study.

Background: There is limited research on the intra-individual efficacy of ventricular pacing minimization algorithms developed by Biotronik-the Ventricular Pace Suppression algorithm (VpS) and the Intrinsic Rhythm Support plus algorithm (IRSplus) (BIOTRONIK SE & Co. KG, Berlin, Germany). We performed a randomized pilot trial that evaluated the efficacy of two algorithms in patients with symptomatic sinus node dysfunction (SND) who received a dual-chamber pacemaker. Methods: The trial was conducted in 11 tertiary hospitals in South Korea. The patients were randomized to either the VpS or IRSplus algorithm group after a 3-month period of fixed atrioventricular (AV) delay. The primary outcome was the ventricular pacing percentage (Vp%) at each follow-up visit. The secondary outcomes were the occurrence of heart failure (HF) and atrial fibrillation (AF) during the study period. Results: Data from 131 patients were analyzed. Initially, their average Vp% over 3 months with a fixed AV interval was 14.1 ± 19.4%. Patients were randomly assigned to VpS and IRSplus groups, with 66 and 65 in each. Algorithms reduced average Vp% to 4.0 ± 11.3% at 9 months and 6.7 ± 14.9% at 15 months. These algorithms were more effective for patients with paced AV delay (PAVD) ≤300 ms compared to those with PAVD >300 ms. Both algorithms were equally effective in reducing Vp%. Clinical AF or HF hospitalization was not observed during the study period. Conclusion: The VpS and IRSplus algorithms are effective and safe in minimizing unnecessary ventricular pacing in patients with SND.

Long-term luminal change after drug-eluting stent implantation: serial angiographic follow-up study of the ZEST randomized trial.

OBJECTIVE: To evaluate long-term patterns of luminal changes after implantation of different types of drug-eluting stents (DES), we analyzed the serial angiographic outcomes of patients implanted with zotarolimus-eluting stents (ZES), sirolimus-eluting stents (SES), or paclitaxel-eluting stents (PES). BACKGROUND: Little is known regarding long-term luminal changes after DES implantation. METHODS: As a subgroup analysis of the ZEST trial, we performed complete angiographic evaluation immediately after the procedure and at 9 months and 2 years in 111 patients with 165 lesions (36 patients with ZES, 40 with SES, and 35 with PES). RESULTS: Baseline clinical, angiographic, and procedural characteristics were similar among the three groups. Quantitative angiographic analysis revealed significant decreases in minimal luminal diameter 9 months after stent implantation in the ZES (from 2.71 ± 0.49 to 2.21 ± 0.42 mm, P < 0.001), SES (from 2.79 ± 0.49 to 2.58 ± 0.57 mm, P < 0.001), and PES (from 2.66 ± 0.45 to 2.19 ± 0.52 mm, P < 0.001) groups. However, significant late improvements with different degree in luminal diameter were observed between 9 months and 2 years in the ZES (from 2.21 ± 0.42 to 2.39 ± 0.58 mm, P = 0.001), SES (from 2.58 ± 0.57 to 2.66 ± 0.60 mm, P = 0.039), and PES (from 2.19 ± 0.52 to 2.43 ± 0.52 mm, P < 0.001) groups. CONCLUSION: Serial angiographic follow-up study revealed a biphasic luminal response after DES implantation, characterized by an early progression phase for the first 9 months and a late regression phase from 9 months to 2 years.

Coronary sinus activation pattern in the differential diagnosis of regular atrial tachyarrhythmias during catheter ablation of atrial fibrillation.

BACKGROUND: Prompt diagnosis and management of atrial tachyarrhythmias (ATAs) during catheter ablation of atrial fibrillation (AF) is still challenging. METHODS AND RESULTS: In 88 patients undergoing catheter ablation of AF, 128 regular ATAs were induced or converted from AF. The coronary sinus activation time (CSAT) around the mitral annulus (MA) was measured as the difference in activation time between the most proximal and distal poles of the coronary sinus (CS) electrodes. Entrainment pacing was performed around the MA, roof area, or cavotricuspid isthmus (CTI) depending on the CSAT result. Mechanisms of tachycardias included macro-reentry around the MA (perimitral atrial flutter [PM-AFL], n=63), roof-dependent AFL (Roof-AFL, n=14), CTI-dependent AFL (CTI-AFL, n=25), and atrial tachycardia (AT, n=26). When the CSAT was ≥ 45 ms, the MA activation sequence was sequential, either proximal to distal or distal to proximal. When the CSAT was <45 ms, the MA activation sequence was mainly non-sequential with converging or diverging patterns. CSAT <45 ms was highly sensitive in ruling out PM-AFL from other left ATAs. When combined with PPI data from the MA, roof area or CTI, PM-, Roof-, CTI-AFL and AT was successfully differentiated with a high predictive accuracy. CONCLUSIONS: A diagnostic algorithm combining CSAT and entrainment pacing is helpful to assess the mechanism of ATAs during catheter ablation of AF.

Standard-Intensity Versus Low-Intensity Anticoagulation with Warfarin in Asian Patients with Atrial Fibrillation: A Multi-Center, Randomized Controlled Trial.

Anticoagulation with warfarin in Asian patients with atrial fibrillation (AF) often has been decreased as an international normalized ratio (INR) of prothrombin time 1.6-2.6 due to fear of bleeding, although universal criteria recommend an INR of 2.0-3.0. In this randomized, open-label trial, low-intensity anticoagulation (INR 1.6-2.6) was compared with standard-intensity anticoagulation (INR 2.0-3.0) with warfarin. A total 616 patients with AF and at least 1 risk factor for stroke were randomized to low-intensity anticoagulation (n = 308) and standard-intensity anticoagulation (n = 308) groups. The intention-to-treat analysis was performed to determine differences. The baseline characteristics of the two groups were comparable. New-onset stroke occurred in 2 patients (0.44% per year) in the low-intensity group and 5 patients (1.05% per year) in the standard-intensity group (HR 0.42, 95% CI 0.08-2.15). Major bleeding occurred in 4 patients (0.89% per year) in the low-intensity group and 5 patients (1.06% per year) in the standard-intensity group (HR 0.84, 95% CI 0.22-3.11). The rate of the net clinical outcome (composite of stroke, systemic embolism, major bleeding, and death) was 1.33% per year in the low-intensity group compared with 2.12% per year in the standard-intensity group (HR 0.63, 95% CI 0.23-1.72). In Asian patients with AF, clinical outcomes were not different between low-intensity and standard-intensity anticoagulation with warfarin.

Cerebral blood flow as a marker for recovery of left ventricular systolic dysfunction in patients with idiopathic dilated cardiomyopathy.

BACKGROUND: This study was intended to investigate whether cerebral blood flow (CBF) could predict the recovery of left ventricular (LV) systolic dysfunction in patients with idiopathic dilated cardiomyopathy (DCMP). METHODS AND RESULTS: Between July 2001 and March 2009, 107 patients who had been diagnosed with idiopathic DCMP underwent radionuclide angiography to assess their CBF. The recovery of LV systolic dysfunction was defined as recovery of the ejection fraction (EF) measured by transthoracic echocardiography to a level of 40% or greater and an increase of 10% or greater in its absolute value during follow-up. The EF was followed for at least 36 months if it did not recover. Thirty-four patients (31.8%) recovered and had greater CBF than the nonrecovered patients (41.9 ± 3.4 vs. 37.1 ± 4.9 mL/min/100g, P < .001). On multivariate logistic analysis, CBF (odds ratio 1.216) and symptom duration (odds ratio 0.952) were independent predictors of the recovery of LV systolic dysfunction. There was also a weak negative correlation between CBF and symptom duration (r = -0.334, P < .001). Furthermore, CBF was associated with LVEF improvement seen at the 1- and 2-year follow-up times according to multiple linear regression analysis. CONCLUSIONS: CBF was associated with recovery of LV systolic dysfunction in patients with idiopathic DCMP. Therefore, measurement of CBF would be helpful to predict the clinical course of their disease.

Somatic mutations of the KEAP1 gene in common solid cancers.

AIMS: KEAP1 inhibits nuclear factor erythroid 2-related factor 2 (NRF2)-induced cytoprotection, and is considered to be a candidate tumour suppressor. Somatic mutation of NRF2 has been analysed in a wide variety of human cancers, whereas somatic mutation of KEAP1 has been reported only in lung and gall bladder cancers. The aim of our study was to investigate whether KEAP1 mutations are widespread in human cancers. METHODS AND RESULTS: We analysed 499 cancer tissues from lung, breast, colon, stomach, liver, larynx and prostate, and leukaemias, by single-strand conformation polymorphism analysis. We detected somatic mutations of KEAP1 in gastric (11.1%), hepatocellular (8.9%), colorectal (7.8%), lung (4.6%), breast (2.0%) and prostate (1.3%) carcinomas. Allelic losses of the KEAP1 locus were identified in 42.9% of cancers with KEAP1 mutations, but no NRF2 mutations were detected in these cancers. The NRF2-activated cytoprotective proteins (NAD(P)H dehydrogenase quinone 1 and glutamine-cysteine ligase catalytic subunit) were expressed in all of the cancers with KEAP1 mutations. CONCLUSIONS: Our data show that KEAP1 mutations occur widely in solid cancers, irrespective of histological type. Biallelic inactivation of KEAP1 and increased levels of cytoprotective proteins in the cancers suggest that KEAP1 mutations might protect cancer cells from oxidative insults and play a role in the development of solid cancers.

Somatic mutation of PHF6 gene in T-cell acute lymphoblatic leukemia, acute myelogenous leukemia and hepatocellular carcinoma.

INTRODUCTION: Somatic mutations in plant homeodomain finger protein 6 (PHF6) gene have recently been reported in T-cell acute lymphoblastic leukemia (T-ALL), strongly suggesting its role in the pathogenesis of human cancers. MATERIALS AND METHODS: To see whether the PHF6 mutation occurs in other malignancies, we analyzed entire coding sequences of PHF6 in 231 hematologic malignancies [105 acute myelogenous leukemias (AML), 66 pre-B-ALL, 23 T-ALL, one undifferentiated acute leukemia and 36 multiple myelomas] by single-strand conformation polymorphism assay. Also, we analyzed the mutation in 236 solid cancers, including 41 lung, 39 hepatocellular (HCC), 36 breast, 40 colorectal, 40 gastric and 40 prostate carcinomas. RESULTS: In the hematologic malignancies, there were 11 PHF6 mutations that were detected not only in T-ALL (34.7%) (five adult and three childhood T-ALL), but also in two AML (1.9%) (one acute monocytic leukemia and one AML minimally differentiated). In addition, there was a PHF6 mutation in the HCC (2.6%). The PHF6 mutations were detected in both male and female patients, and consisted of six frameshift, three nonsense and two intron mutations. CONCLUSION: Our data suggest that PHF6 mutation might play a role in tumorigenesis not only of T-ALL, but also of AML and HCC.

Corrigendum to "Covid-19 and the aviation industry: The interrelationship between the spread of the Covid-19 pandemic and the frequency of flights on the EU Market" [Ann. Tour. Res., Volume 91, November 2021, 103298].

[This corrects the article DOI: 10.1016/j.annals.2021.103298.].

Prevalence and Characteristics of Atrial Tachycardia From Noncoronary Aortic Cusp During Atrial Fibrillation Catheter Ablation.

BACKGROUND AND OBJECTIVES: Atrial tachycardias (ATs) from noncoronary aortic cusp (NCC) uncovered after radiofrequency ablation for atrial fibrillation (AF) are rarely reported. This study was conducted to investigate the prevalence and clinical characteristics of NCC ATs detected during AF ablation and compare their characteristics with de novo NCC ATs without AF. METHODS: Consecutive patients who underwent radiofrequency catheter ablation for AF were reviewed from the multicenter AF ablation registry of 11 tertiary hospitals. The clinical and electrophysiological characteristics of NCC AT newly detected during AF ablation were compared with its comparators (de novo NCC AT ablation cases without AF). RESULTS: Among 10,178 AF cases, including 1,301 redo ablation cases, 8 (0.08%) NCC AT cases were discovered after pulmonary vein isolation (PVI; 0.07% in first ablation and 0.15% in redo ablation cases). All ATs were reproducibly inducible spontaneously or with programmed atrial stimulation without isoproterenol infusion. The P-wave morphological features of tachycardia were variable depending on the case, and most cases exhibited 1:1 atrioventricular conduction. AF recurrence rate after PVI and NCC AT successful ablation was 12.5% (1 of 8). Tachycardia cycle length was shorter than that of 17 de novo ATs from NCC (303 versus 378, p=0.012). No AV block occurred during and after successful AT ablation. CONCLUSIONS: Uncommon NCC ATs (0.08% in AF ablation cases) uncovered after PVI, showing different characteristics compared to de-novo NCC ATs, should be suspected irrespective of P-wave morphologies when AT shows broad propagation from the anterior interatrial septum.

Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin.

Nuclear factor erythroid-related factor 2 (NRF2) encodes a transcription factor that induces expression of cytoprotective proteins upon oxidative stress and oncogenic NRF2 mutations have been found in lung and head/neck cancers that inactivate KEAP1-mediated degradation of NRF2. The aim of this study was to catalogue NRF2 mutations in other human cancers. For this, we analysed 1145 cancer tissues from carcinomas from oesophagus, skin, uterine cervix, lung, larynx, breast, colon, stomach, liver, prostate, urinary bladder, ovary, uterine cervix, and kidney, and meningiomas, multiple myelomas, and acute leukaemias by single-strand conformation polymorphism (SSCP) assay. We detected NRF2 mutations in oesophagus (8/70; 11.4%), skin (1/17; 6.3%), lung (10/125; 8.0%), and larynx (3/23; 13.0%) cancers. Of note, all of the 22 mutations except one were found in squamous cell carcinomas (SCCs) (95.5%). The mutations were observed within or near DLG and ETGE motifs that are important in NRF2 and KEAP1 interaction. All of the oesophageal SCCs and skin SCCs with the NRF2 mutations showed increased NRF2 expression in the nuclei. However, none of the SCCs from oesophagus and skin harboured KEAP1 mutation. Our study demonstrated here that NRF2 mutation occurs not only in lung and head/neck cancers, but also in oesophageal and skin cancers. Our data suggest that the NRF2 mutation plays a role in the development of SCC and is a feature of SCC.

Expression of AIMP1, 2 and 3, the scaffolds for the multi-tRNA synthetase complex, is downregulated in gastric and colorectal cancer.

Aminoacyl-tRNA synthetase-interacting multifunctional proteins (AIMPs) form a protein complex with aminoacyl-tRNA synthetases. In addition to protein translation, AIMPs play a role in diverse biological processes. Earlier studies suggested that AIMPs may act as tumor suppressors. However, the expression status of the AIMP proteins in human cancer tissues is largely unknown. In this study, we analyzed the expression of AIMP members (AIMP1, AIMP2 and AIMP3) in gastric cancer (GC) and colorectal cancer (CRC) tissues. We analyzed the expression of these proteins in 100 GC and 103 CRC tissues by immunohistochemistry using a tissue microarray method. Normal gastric and colon mucosa expressed AIMP1, AIMP2 and AIMP3 in nearly all of the cases (95-100%). However, the expression of AIMP1, AIMP2 and AIMP3 was significantly decreased in the GC samples (60%, 52% and 70% of the cases, respectively) and in the CRC samples (66%, 53% and 81% of the cases, respectively) ( P <0.01). Expression of AIMP1, AIMP2 or AIMP3 was not associated with clinicopathological parameters including differentiation, depth of invasion and TNM stage. The decreased expression of AIMP1, AIMP2 and AIMP3 in the GC and CRC tissues compared to the corresponding normal tissues suggested that downregulation of these proteins may be related to inactivation of the tumor suppressor functions of AIMP proteins and might play a role in the development of GC and CRC.