Integrin α5 regulates motility of human monocyte-derived Langerhans cells during immune response.

Langerhans cells (LCs) are mainly present in the epidermis and mucosa, and have important roles during skin infection. Migration of LCs to lymph nodes is essential for antigen presentation. However, due to the difficulties in isolating and culturing human LCs, it is not fully understood how LCs move and interact with the extracellular matrix (ECM) through their adhesion molecules such as integrin, during the immune responses. In this study, we aimed to investigate LC motility, cell shape and the role of integrin under inflammatory conditions using monocyte-derived Langerhans cells (moLCs) as a model. As a result, lipopolysaccharide (LPS) stimulation increased adhesion on fibronectin coated substrate and integrin α5 expression in moLCs. Time-lapse imaging of moLCs revealed that stimulation with LPS elongated cell shape, whilst decreasing their motility. Additionally, this decrease in motility was not observed when pre-treated with a neutralising antibody targeting integrin α5. Together, our data suggested that activation of LCs decreases their motility by promoting integrin α5 expression to enhance their affinity to the fibronectin, which may contribute to their migration during inflammation.

Roles of TRPM4 in immune responses in keratinocytes and identification of a novel TRPM4-activating agent.

The skin is a protective interface between the internal organs and environment and functions not only as a physical barrier but also as an immune organ. However, the immune system in the skin is not fully understood. A member of the thermo-sensitive transient receptor potential (TRP) channel family, TRPM4, which acts as a regulatory receptor in immune cells, was recently reported to be expressed in human skin and keratinocytes. However, the function of TRPM4 in immune responses in keratinocytes has not been investigated. In this study, we found that treatment with BTP2, a known TRPM4 agonist, reduced cytokine production induced by tumor necrosis factor (TNF) α in normal human epidermal keratinocytes and in immortalized human epidermal keratinocytes (HaCaT cells). This cytokine-reducing effect was not observed in TRPM4-deficient HaCaT cells, indicating that TRPM4 contributed to the control of cytokine production in keratinocytes. Furthermore, we identified aluminum potassium sulfate, as a new TRPM4 activating agent. Aluminum potassium sulfate reduced Ca2+ influx by store-operated Ca2+ entry in human TRPM4-expressing HEK293T cells. We further confirmed that aluminum potassium sulfate evoked TRPM4-mediated currents, showing direct evidence for TRPM4 activation. Moreover, treatment with aluminum potassium sulfate reduced cytokine expression induced by TNFα in HaCaT cells. Taken together, our data suggested that TRPM4 may serve as a new target for the treatment of skin inflammatory reactions by suppressing the cytokine production in keratinocytes, and aluminum potassium sulfate is a useful ingredient to prevent undesirable skin inflammation through TRPM4 activation.

Effect of Catheter Ablation for Atrial Fibrillation in Heart Failure With Mid-Range or Preserved Ejection Fraction　- Pooled Analysis of the AF Frontier Ablation Registry and Hokuriku-Plus AF Registry.

BACKGROUND: A recent randomized trial demonstrated that catheter ablation for atrial fibrillation (AF) in patients with heart failure with reduced ejection fraction (EF) is associated with a reduction in death or heart failure. However, the effect of catheter ablation for AF in patients with heart failure with mid-range or preserved EF is unclear.Methods and Results: We screened 899 AF patients (72.4% male, mean age 68.4 years) with heart failure and left ventricular EF ≥40% from 2 Japanese multicenter AF registries: the Atrial Fibrillation registry to Follow the long-teRm Outcomes and use of aNTIcoagulants aftER Ablation (AF Frontier Ablation Registry) as the ablation group (525 patients who underwent ablation) and the Hokuriku-Plus AF Registry as the medical therapy group (374 patients who did not undergo ablation). Propensity score matching was performed in these 2 registries to yield 106 matched patient pairs. The primary endpoint was a composite of cardiovascular death and hospitalization for heart failure. At 24.6 months, the ablation group had a significantly lower incidence of the primary endpoint (hazard ratio 0.32; 95% confidence interval 0.13-0.70; P=0.004) than the medical therapy group. CONCLUSIONS: Compared with medical therapy, catheter ablation for AF in patients with heart failure and mid-range or preserved EF was associated with a significantly lower incidence of cardiovascular death or hospitalization for heart failure.

Comparison between cryoballoon double stop and single stop in patients with paroxysmal atrial fibrillation.

BACKGROUND: Currently, cryoballoon (CB) thawing after single stop is generally performed. Previous research had reported that long thawing time using a single stop affects pulmonary veins tissue injury. However, it is uncertain whether CB thawing after single stop affects clinical outcomes. OBJECTIVE: This study aimed to clarify clinical significance of CB thawing in patients with paroxysmal atrial fibrillation. METHODS: Two hundred ten patients with paroxysmal atrial fibrillation who underwent CB from January 2018 to October 2019 were analyzed. We compared the clinical outcomes of patients whose CB applications were completely stopped with only the double stop technique (DS group, n = 99) and patients with single stop (SS group, n = 111). In DS group, we performed double stop technique for all CB application regardless of phrenic nerve injury or the temperature of esophagus. RESULTS: The atrial arrhythmia free-survival rate at 2 years after CB was significantly lower for the DS group than the SS group (76.8% vs 87.4%; p = 0.045). Complications occurred in 2 patients from the DS group and no complications were observed in patients from the SS group (p = 0.13). Mean procedural time was shorter in the DS group than in the SS group (53.1 vs 58.1 min; p = 0.046) CONCLUSION: DS group had higher recurrence rate than SS group. There was no significant difference regarding safety between both the groups. We found that the thawing process after single stop is very important for CB application.

Different Determinants of the Recurrence of Atrial Fibrillation and Adverse Clinical Events in the Mid-Term Period After Atrial Fibrillation Ablation.

BACKGROUND: It is unclear whether there are differences in the clinical factors between atrial fibrillation (AF) recurrence and adverse clinical events (AEs), including stroke/transient ischemic attack (TIA), major bleeding, and death, after AF ablation.Methods and Results:We examined the data from a retrospective multicenter Japanese registry conducted at 24 cardiovascular centers between 2011 and 2017. Of the 3,451 patients (74.1% men; 63.3±10.3 years) who underwent AF ablation, 1,046 (30.3%) had AF recurrence and 224 (6.5%) suffered AEs (51 strokes/TIAs, 71 major bleeding events, and 36 deaths) over a median follow-up of 20.7 months. After multivariate adjustment, female sex, persistent and long-lasting persistent AF (vs. paroxysmal AF), and stepwise increased left atrial diameter (LAd) quartiles were significantly associated with post-ablation recurrences. A multivariate analysis revealed that an age ≥75 years (vs. <65 years), body weight <50 kg, diabetes, vascular disease, left ventricular (LV) ejection fraction <40% (vs. ≥50%), Lad ≥44 mm (vs. <36 mm), and creatinine clearance <50 mL/min were independently associated with AE incidences, but not with recurrences. CONCLUSIONS: This study disclosed different determinants of post-ablation recurrence and AEs. Female sex, persistent AF, and enlarged LAd were determinants of post-ablation recurrence, whereas an old age, comorbidities, and LV and renal dysfunction rather than post-ablation recurrence were AEs determinants. These findings will help determine ablation indications and post-ablation management.

Serum Globulin Is Associated with Endoscopic Findings and Mucosal Healing in Japanese Patients with Ulcerative Colitis.

BACKGROUND: Serum globulin is an inflammation marker. To date, no evidence regarding the association between serum globulin and disease activity in patients with ulcerative colitis has been reported. AIMS: We evaluated the association between serum globulin and endoscopic activity in patients with ulcerative colitis. METHODS: Serum globulin was divided into tertiles based on the distribution of study subjects (low globulin, ≤ 2.7 g/dl (reference); moderate globulin, 2.7-3.1 g/dl; and high globulin, > 3.1 g/dl). A single endoscopic specialist evaluated the endoscopic findings, and mucosal healing was based on Mayo endoscopic subscore. RESULTS: A total of 277 patients with ulcerative colitis were included in the study. Serum globulin was independently positively associated with diminished or absent vascular markings [moderate: adjusted odds ratio (OR) 3.70 (95% confidence interval, CI: 1.82-7.88) and high: adjusted OR 2.40 (95%CI: 1.20-4.94), p for trend = 0.005]. A similar positive association between globulin and erosion was found [high: adjusted OR 2.00 (95%CI: 1.05-3.86)]. Serum globulin was independently inversely associated with mucosal healing [moderate: adjusted OR 0.37 (95%CI: 0.18-0.73) and high: adjusted OR 0.31 (95%CI: 0.14-0.64), p for trend = 0.001] and adjusted partial mucosal healing [moderate: OR 0.51 (95%CI: 0.26-0.98), p for trend = 0.048]. The inverse association between globulin and mucosal healing was significant in the low but not the high C-reactive protein group. CONCLUSIONS: In patients with ulcerative colitis, serum globulin was significantly positively associated with endoscopic activity, and was significantly inversely associated with mucosal healing, especially in the low C-reactive protein group.

Impact of sinus rhythm maintenance on major adverse cardiac and cerebrovascular events after catheter ablation of atrial fibrillation: insights from AF frontier ablation registry.

The impact of catheter ablation for atrial fibrillation (AF) on cardiovascular events and mortality is controversial. We investigated the impact of sinus rhythm maintenance on major adverse cardiac and cerebrovascular events after AF ablation from a Japanese multicenter cohort of AF ablation. We investigated 3326 consecutive patients (25.8% female, mean age 63.3 ± 10.3 years) who underwent catheter ablation for AF from the atrial fibrillation registry to follow the long-term outcomes and use of anti coagulants after ablation (AF frontier ablation registry). The primary endpoint was a composite of stroke, transient ischemic attack, cardiovascular events, and all-cause death. During a mean follow-up of 24.0 months, 2339 (70.3%) patients were free from AF after catheter ablation, and the primary composite endpoint occurred in 144 (4.3%) patients. The AF nonrecurrence group had a significantly lower incidence of the primary endpoint (1.8 per 100 person-years) compared with the AF recurrence group (3.0 per 100 person-years, p = 0.003). The multivariate analysis revealed that freedom from AF (hazard ratio 0.61, 95% confidence interval 0.44-0.86, p = 0.005) was independently associated with the incidence of the composite event. In the multicenter cohort of AF ablation, sinus rhythm maintenance after catheter ablation was independently associated with lower rates of major adverse cardiac and cerebrovascular events.

Horizontal stent deployment via extracranial-intracranial bypass in coil embolization of basilar apex aneurysms: technical report.

BACKGROUND: The endovascular treatment of large, wide-necked basilar apex aneurysms (BAAs) remains challenging. Although horizontal stent deployment across both P1 segments of the posterior cerebral arteries (PCAs) would be an optimal strategy in coil embolization of wide-necked BAAs, this is only feasible in cases with anatomically favorable access. In rare circumstances, large-diameter conduits of extracranial-intracranial (EC-IC) bypass can also provide a good access route for endovascular treatment of complex intracranial aneurysms. METHODS: We describe the technique of accessing the PCA via EC-IC bypass grafts and deploying a stent horizontally across the neck of BAA and its coil embolization. We provide a detailed technical review and describe some pitfalls of the procedure. RESULTS: Two patients underwent EC-IC bypass surgery prior to the treatment of a large, wide-necked BAA. The radial artery and saphenous vein were used as grafts, respectively. To facilitate coil embolization for a large BAA, a PCA-to-PCA horizontal stent was deployed via the bypass graft. Trans-cell and jailing techniques were used, respectively. Both aneurysms were completely occluded, and the patients were discharged without any neurological deficit. CONCLUSION: Horizontal stent deployment via EC-IC bypass grafts can be performed safely, providing proper closure of the aneurysmal neck and apposition to both PCAs, facilitating complete coil embolization.

Clinical outcomes of ablation versus non-ablation therapy for atrial fibrillation in Japan: analysis of pooled data from the AF Frontier Ablation Registry and SAKURA AF Registry.

Whether ablation for atrial fibrillation (AF) is, in terms of clinical outcomes, beneficial for Japanese patients has not been clarified. Drawing data from 2 Japanese AF registries (AF Frontier Ablation Registry and SAKURA AF Registry), we compared the incidence of clinically relevant events (CREs), including stroke/transient ischemic attack (TIA), major bleeding, cardiovascular events, and death, between patients who underwent ablation (n = 3451) and those who did not (n = 2930). We also compared propensity-score matched patients (n = 1414 in each group). In propensity-scored patients who underwent ablation and those who did not, mean follow-up times were 27.2 and 35.8 months, respectively. Annualized rates for stroke/TIA (1.04 vs. 1.06%), major bleeding (1.44 vs. 1.20%), cardiovascular events (2.15 vs. 2.49%) were similar (P = 0.96, 0.39, and 0.35, respectively), but annualized death rates were lower in the ablation group than in the non-ablation group (0.75 vs.1.28%, P = 0.028). After multivariate adjustment, the risk of CREs was statistically equivalent between the ablation and non-ablation groups (hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.71-1.11), but it was significantly low among patients who underwent ablation for paroxysmal AF (HR 0.68 [vs. persistent AF], 95% CI 0.49-0.94) and had a CHA2DS2-VASc score < 3 (HR 0.66 [vs. CHA2DS2-VASc score ≥ 3], 95% CI 0.43-0.98]). The 2-year risk reduction achieved by ablation may be small among Japanese patients, but AF ablation may benefit those with paroxysmal AF and a CHA2DS2-VASc score < 3.

Comparison between cryoballoon ablation and radiofrequency catheter ablation for atrial fibrillation in patients on hemodialysis.

BACKGROUND: Difficulties are often encountered while controlling atrial fibrillation (AF), especially in hemodialysis (HD) patients. Previous data revealed that cryoballoon ablation (CBA) for treating paroxysmal atrial fibrillation (PAF) was not inferior to radiofrequency ablation (RFA); however, HD patients were excluded in this prior trial. Thus, the efficacy of CBA for HD patients is still unknown. METHODS: This retrospective study analyzed HD patients who underwent catheter ablation (CA) for AF from August 2011 to June 2019. Patients who received CBA (CBA group) and those who received RFA (RFA group) were compared. The primary endpoint was defined as freedom from a composite outcome (a documented recurrence of any atrial tachyarrhythmia or a prescription of antiarrhythmic drugs) at one year after CA. RESULTS: The RFA and CBA groups were composed of 21 and 23 patients, respectively. Freedom from a composite outcome was 58.4% in the RFA group and 68.2% in the CBA group (Log-rank: p = 0.571). CONCLUSION: Our results suggest that patients on HD with AF who were treated with CBA tended to have better outcomes than patients treated with RFA. Therefore, CBA could be a suitable ablation method for HD patients.

The efficacy of modified jailed balloon technique for true bifurcation lesions.

OBJECTIVE: To evaluate the short-, long-term clinical and angiographic outcomes after treatment of true bifurcation lesions using a modified jailed balloon technique (MJBT). BACKGROUND: Percutaneous coronary intervention (PCI) for true bifurcation lesions has high risk for adverse events. Side branch (SB) occlusion is one of the most serious complications. Therefore, novel strategies to avoid SB occlusion during main branch stenting and to keep its patency are important. METHODS AND RESULTS: Between February 2015 and February 2018, 328 patients with 349 true bifurcation lesions underwent PCI using MJBT. True bifurcation lesions were defined as Medina classifications (1.1.1), (1.0.1) or (0.1.1) lesions. We investigated the procedural and long-term clinical outcomes. Furthermore, angiographic outcomes were assessed at follow-up diagnostic angiography. The mean age of patients was 71.6 ± 9.9 years. Procedural success was achieved in all patients; postoperative SB occlusion was noted in only one patient (0.3%). The cumulative incidence of all-cause death was 23 patients (7.0%) in the follow-up period (median 717 days). Target lesion revascularization was performed in 19 patients (5.8%) with 23 lesions (6.6%), and 0.6% of myocardial infarction and 0% of definite stent thrombosis were observed. Angiographic follow-up was performed in 243 patients (74.1%); the percent diameter stenosis in SB was not significantly different between after the index procedure and follow-up angiography. CONCLUSIONS: This MJBT is safe and effective in preserving SB patency for true bifurcation lesions. Furthermore, long-term clinical and angiographic outcomes after MJBT are feasible.

Association between platelet count and mucosal healing in Japanese patients with ulcerative colitis: a cross-sectional study.

BACKGROUND: Mucosal healing (MH) has been indicated as the therapeutic goal for ulcerative colitis (UC). Platelet count is known as an inflammation evaluation. However, the association between platelet count and MH among patients with UC is still scarce. We therefore assessed this issue among Japanese patients with UC. METHODS: The study subjects consisted of 345 Japanese patients with UC. Platelet count was divided into quartiles on the basis of the distribution of all study subjects (low, moderate, high, and very high). Several endoscope specialists were responsible for evaluating MH and partial MH, which was defined as a Mayo endoscopic subscore of 0 and 0-1, respectively. Estimations of crude odds ratios (ORs) and their 95% confidence intervals (CIs) for partial MH and MH in relation to platelet count were performed using logistic regression analysis. Age, sex, CRP, steroid use, and anti-Tumor necrosis factor α (TNFα) preparation were selected a priori as potential confounding factors. RESULTS: The percentage of partial MH and MH were 63.2 and 26.1%, respectively. Moderate and very high was independently inversely associated with partial MH (moderate: OR 0.40 [95%CI 0.19-0.810], very high: OR 0.37 [95%CI 0.17-0.77], p for trend = 0.034). Similarly, moderate, high, and very high were independently inversely associated with MH (moderate: OR 0.37 [95% CI 0.18-0.73], high: OR 0.41 [95% CI 0.19-0.83], and very high: OR 0.45 [95% CI 0.21-0.94], p for trend = 0.033) after adjustment for confounding factors. CONCLUSIONS: Among patients with UC, platelet count was independently inversely associated with MH.

Impact of bleeding events after percutaneous coronary intervention in patients on hemodialysis.

Coronary artery disease is common in patients on dialysis; there is a high rate of bleeding events after percutaneous coronary intervention (PCI) in such patients. We investigated the impact of bleeding events after PCI on mortality in patients on hemodialysis. We included 386 consecutive hemodialysis patients who underwent PCI using a drug-eluting stent (DES) between September 2004 and December 2017 in our hospital, and investigated the impact of bleeding events on all-cause mortality after PCI. Bleeding events were assessed by the Thrombolysis in Myocardial Infarction (TIMI) bleeding definition within 24 months after PCI. A total of 42 patients experienced bleeding events. Of these, 30 patients (71.4%) had TIMI major bleeding events and 12 patients (28.6%) had TIMI minor bleeding events. Patients with bleeding events had significantly higher mortality than patients without bleeding events (survival rate, 55.1% vs 81.5%, log-rank: p < 0.001). These results suggest that bleeding events after PCI with a DES are notably associated with all-cause mortality among patients on hemodialysis. This is the first report about relationship between bleeding events and mortality to focus on patients on hemodialysis.

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf-/- mouse model.

Inhibitors of double minute 2 protein (MDM2)-tumor protein 53 (TP53) interaction are predicted to be effective in tumors in which the TP53 gene is wild type, by preventing TP53 protein degradation. One such setting is represented by the frequent CDKN2A deletion in human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades TP53 tumor suppressor. Here we used piggyBac (PB) transposon insertional mutagenesis to anticipate resistance mechanisms occurring during treatment with the MDM2-TP53 inhibitor HDM201. Constitutive PB mutagenesis in Arf-/- mice provided a collection of spontaneous tumors with characterized insertional genetic landscapes. Tumors were allografted in large cohorts of mice to assess the pharmacologic effects of HDM201. Sixteen out of 21 allograft models were sensitive to HDM201 but ultimately relapsed under treatment. A comparison of tumors with acquired resistance to HDM201 and untreated tumors identified 87 genes that were differentially and significantly targeted by the PB transposon. Resistant tumors displayed a complex clonality pattern suggesting the emergence of several resistant subclones. Among the most frequent alterations conferring resistance, we observed somatic and insertional loss-of-function mutations in transformation-related protein 53 (Trp53) in 54% of tumors and transposon-mediated gain-of-function alterations in B-cell lymphoma-extra large (Bcl-xL), Mdm4, and two TP53 family members, resulting in expression of the TP53 dominant negative truncations ΔNTrp63 and ΔNTrp73. Enhanced BCL-xL and MDM4 protein expression was confirmed in resistant tumors, as well as in HDM201-resistant patient-derived tumor xenografts. Interestingly, concomitant inhibition of MDM2 and BCL-xL demonstrated significant synergy in p53 wild-type cell lines in vitro. Collectively, our findings identify several potential mechanisms by which TP53 wild-type tumors may escape MDM2-targeted therapy.

Clinical Outcomes of Off-Label Underdosing of Direct Oral Anticoagulants After Ablation for Atrial Fibrillation.

Direct oral anticoagulants (DOACs) are sometimes prescribed at off-label under-doses for patients who have undergone ablation for atrial fibrillation (AF). This practice may be an attempt to balance the risk of bleeding against that of stroke or AF recurrence.We examined outcomes of 1163 patients who continued use of a DOAC after ablation. The patients were enrolled in a large (3530 patients) multicenter registry in Japan. The study patients were classified as 749 (64.4%) appropriate standard-dose DOAC users, 216 (18.6%) off-label under-dose DOAC users, and 198 (17.0%) appropriate low-dose DOAC users.Age and CHA2DS2-VASc scores differed significantly between DOAC dosing regimens, with patients given an appropriate standard-dose being significantly younger (63.3 ± 9.4 versus 64.8 ± 9.5 versus 73.2 ± 6.8 years, P < 0.0001) and lower (2.1 ± 1.5 versus 2.4 ± 1.6 versus 3.4 ± 1.4, P < 0.0001) than those given an off-label under-dose or an appropriate low-dose. During the median 19.0-month follow-up period, the AF recurrence rate was similar between the appropriate standard-dose and off-label under-dose groups but relatively low in the appropriate low-dose group (42.5% versus 41.2% versus 35.4%, P = 0.08). Annualized rates of thromboembolic events, major bleeding, and death from any cause were 0.47%, 0.70%, and 0.23% in the off-label under-dose group, while those rates were 0.74%, 0.73%, and 0.65% in the appropriate standard-dose, and 1.58%, 2.12%, and 1.57% in the appropriate low-dose groups.In conclusion, the clinical adverse event rates for patients on an off-label under-dose DOAC regimen after ablation, predicated on careful patient evaluations, was not high as seen with that of patients on a standard DOAC dosing regimen.

Impact of Late Ventricular Arrhythmias on Cardiac Mortality in Patients with Acute Myocardial Infarction.

OBJECTIVES: This study investigated the relationship between the timing of ventricular tachycardia or ventricular fibrillation (VT or VF) and prognosis in patients undergoing primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). BACKGROUND: It is unknown whether the timing of VT/VF occurrence affects the prognosis of patients with AMI. METHODS: From January 2004 to December 2014, 1004 patients with AMI underwent primary PCI. Of these patients, 888 did not have VT/VF (non-VT/VF group) and 116 had sustained VT/VF during prehospitalization or hospitalization. Patients with VT/VF were divided into two groups: early VT/VF (VT/VF occurrence before and within 2 days of admission, 92 patients) and late VT/VF (VT/VF occurrence >2 days after admission; 24 patients) groups. RESULTS: The frequency of VT/VF occurrence was high between the day of admission and the 2nd day and between days 6 and 10 of hospitalization. The late VT/VF group had a significantly longer onset-to-balloon time, lower ejection fraction, poorer renal function, and higher creatine phosphokinase (CK)-MB level on admission (p< 0.001). They also had a lower 30-day cardiac survival rate than the early VT/VF and non-VT/VF groups (42% vs. 76% vs. 96%, p < 0.001). Moreover, independent predictors of in-hospital cardiac mortality among patients with AMI who had sustained VT/VF were higher peak CK-MB [Odds ratio (OR: 1.001, 95%confidence interval (CI): 1.000-1.002, p= 0.03)], higher Killip class (OR: 1.484, 95%CI 1.017-2.165, p= 0.04), and late VT/VF (OR: 3.436, 95%CI 1.115-10.59, p= 0.03). CONCLUSIONS: The timing of VT/VF occurrences had a bimodal peak. Although late VT/VF occurrence after primary PCI was less frequent than early VT/VF occurrence, patients with late VT/VF had a very poor prognosis.

Current Status and Clinical Outcomes of Oral Anticoagulant Discontinuation After Ablation for Atrial Fibrillation in Japan　- Findings From the AF Frontier Ablation Registry.

BACKGROUND: The safety of discontinuing oral anticoagulant (OAC) after ablation for atrial fibrillation (AF) in Japanese patients has not been clarified.Methods and Results:A study based on the Atrial Fibrillation registry to Follow the long-teRm Outcomes and use of aNTIcoagulants aftER Ablation (AF Frontier Ablation Registry) was conducted. Data were collected from 3,451 consecutive patients (74.1% men; age, 63.3±10.3 years) who had undergone AF ablation at any of 24 cardiovascular centers in Japan between August 2011 and July 2017. During a 20.7-month follow-up period, OAC therapy was discontinued in 1,836 (53.2%) patients; 51 patients (1.5%) suffered a stroke/transient ischemic attack (TIA), 71 (2.1%) suffered major bleeding, and 36 (1.0%) died. Patients in whom OAC therapy was discontinued were significantly younger than those in whom OACs were continued, and their CHA2DS2-VASc scores were significantly lower. The incidences of stroke/TIA, major bleeding, and death were significantly lower among these patients. Upon multivariate adjustment, stroke events were independently associated with relatively high baseline CHA2DS2-VASc scores but not with OAC status. CONCLUSIONS: Although the incidences of stroke/TIA, major bleeding, and death were relatively low among patients for whom OAC therapy was discontinued, stroke/TIA occurrence was strongly associated with a high baseline stroke risk rather than with OAC status. Thus, discontinuation of OAC therapy requires careful consideration, especially in patients with a high baseline stroke risk.

Clinical experience of idarucizumab use in cases of cardiac tamponade under uninterrupted anticoagulation of dabigatran during catheter ablation of atrial fibrillation.

Anticoagulants are prescribed for prevention of thromboembolic events (TE) of atrial fibrillation (AF), however, their effects have a negative impact on disastrous bleeding outcomes. Idarucizumab was developed to reverse the anticoagulation effects of dabigatran. This study aimed to retrospectively investigate the clinical efficacy and safety of idarucizumab in the setting of progressive emergent bleeding events associated with catheter ablation (CA). Dabigatran is given uninterruptedly as an anticoagulant in patients undergoing CA of AF. The capacity of idarucizumab to reverse the anticoagulant effects of dabigatran in patients with cardiac tamponade associated with CA was examined by measuring the activated partial thromboplastin time (aPTT), active clotting time (ACT), and prothrombin international normalizing ratio (PT-INR). The primary endpoint was effective hemostasis. This analysis included 21 patients receiving idarucizumab, given for restoration of hemostasis. In all 21 patients, hemostasis was restored at a median of 205.6 ± 14.8 min. Normal intraoperative cessation of bleeding was reported in 16 patients, and completion of hemostasis was also ascertained in the remaining four within 5 h. No TEs occurred within 72 h after the idarucizumab administration. Despite a significant reduction in the aPTT and ACT, no significant change was observed in PT-INR after administering idarucizumab. In emergency situations, idarucizumab was able to reverse dabigatran within a relatively short period without any serious adverse events.

Impact of premature activation of the right ventricle with programmed stimulation in Brugada syndrome.

BACKGROUND: In Brugada syndrome (BrS), it has been reported that delayed activation in the RV is related to the development of type-1 ECG, which is more critical than type-2. On the other hand, the coexistence of complete right bundle-branch block (CRBBB), which also causes delayed activation in the RV, sometimes makes typical BrS ECG misleading. We hypothesized that premature stimulation of the RV can unmask the influence of delayed activation in the RV and convert the morphology of ECG in BrS patients. METHODS AND RESULTS: In 35 BrS patients with type-1 ECG including 8 patients with concomitant CRBBB and 6 control subjects with CRBBB, progressively premature single stimulations were delivered from the RV apex on electrophysiological study. Then we evaluated QRS morphology of fusion beats created by single premature stimulation in each patient. In 29 (83%) of 35 of the BrS patients, conversion from type-1 to type-2 ECG was observed during the process of single premature stimulation. Additionally, in all 8 BrS patients with concomitant CRBBB, type-1 or type-2 BrS ECG was revealed by premature stimulation with relief of CRBBB. These findings were not observed in any of the control subjects with CRBBB. CONCLUSION: Single premature stimulation of the RV converts ECG from type-1 to type-2 in most BrS cases and unmasks type-1 ECG in all BrS cases with CRBBB. Our results could suggest that type-1 ECG is associated with delayed activation of the RV compared with type-2 ECG.

JAK2 exon 12 mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis.

Mutations in JAK2 exon 12 are frequently found in patients with polycythemia vera (PV) that do not carry a JAK2-V617F mutation. The majority of these patients display isolated erythrocytosis. We generated a mouse model that expresses JAK2-N542-E543del, the most frequent JAK2 exon 12 mutation found in PV patients. Mice expressing the human JAK2-N542-E543del (Ex12) showed a strong increase in red blood cell parameters but normal neutrophil and platelet counts, and reduced overall survival. Erythropoiesis was increased in the bone marrow and spleen, with normal megakaryopoiesis and absence of myelofibrosis in histopathology. Erythroid progenitors and precursors were increased in hematopoietic tissues, but the numbers of megakaryocytic precursors were unchanged. Phosphorylation Stat3 and Erk1/2 proteins were increased, and a trend toward increased phospho-Stat5 and phospho-Stat1 was noted. However, Stat1 knock out in Ex12 mice induced no changes in platelet or red cell parameters, indicating that Stat1 does not play a central role in mediating the effects of Ex12 signaling on megakaryopoiesis or erythropoiesis. Ex12 mice showed decreased expression of hepcidin and increased expression of transferrin receptor-1 and erythroferrone, suggesting that the strong erythroid phenotype in Ex12 mutant mice is favored by changes in iron metabolism that optimize iron availability to allow maximal production of red cells.