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Background: Although the anterior and posterior boundaries of cavotricuspid isthmus-dependent atrial flutter (AFL) are reported to be located at the tricuspid annulus and sinus venosa region or crista terminalis, the exact upper turnaround point of the AFL circuit remains unclear. The aim of this study was to determine the upper turnaround site of the AFL circuit by means of three-dimensional (3D) mapping and entrainment pacing.Methods: Subjects were 21 patients with counter-clockwise AFL in whom high-density mapping of the high right atrium (RA) and superior vena cava (SVC) orifice was performed with an electroanatomical or non-contact mapping system. Entrainment pacing was performed around the SVC-RA junction.Results: In 20 of the 21 patients, the wavefront from the septal RA split into two wavefronts: one that traveled anterior to the SVC and another that traveled to the posterior RA where it was blocked. In the remaining patient, the wavefront from the septal RA split into two wavefronts: one that propagated through the anterior portion of the SVC orifice and another that propagated transversely across the posterior portion of the SVC orifice. The two wavefronts joined in the lateral RA. Entrainment pacing from the SVC-RA junction demonstrated that the anterior boundary was within the circuit in all patients, but the posterior boundary also constituted a circuit in four patients.Conclusions: We surmise that the upper turnaround site of the AFL circuit is located in the anterior portion of the SVC-RA junction in the majority of patients with AFL. [ABSTRACT FROM AUTHOR]

Whether the activation sequence of the right or left atrium plays a role in the morphology of the flutter wave in common atrial flutter is not completely understood. We present two patients with common counterclockwise atrial flutter in whom changes in the left atrial activation sequence produced significant changes in flutter wave polarity (+ to - and - to -/+ biphasic) without a change in the activation sequence within the right atrium. These cases highlight the possible role of alterations of the interatrial connections in the genesis of atypical manifestations of common atrial flutter. [ABSTRACT FROM AUTHOR]

Background: Obesity-associated asthma is a phenotype of severe asthma. Late-onset, non-eosinophilic and female-dominant phenotype is highly symptomatic and difficult to treat. Leptin, an adipokine, exerts an immunomodulatory effect. IL-33 associated with innate immunity induces type 2 inflammation and is present in adipose tissue. The purpose of this study was to elucidate the pathogenesis of obesity-associated asthma by focusing on the interaction between leptin and IL-33., Methods: In leptin-deficient obese (ob/ob) and wild-type mice, IL-33 was instilled intranasally on three consecutive days. In part of the mice, leptin was injected intraperitoneally prior to IL-33 treatment. The mice were challenged with methacholine, and airway hyperresponsiveness (AHR) was assessed by resistance (Rrs) and elastance (Ers) of the respiratory system using the forced oscillation technique. Cell differentiation, IL-5, IL-13, eotaxin, keratinocyte-derived chemokine (KC) in bronchoalveolar lavage fluid (BALF) and histology of the lung were analyzed. For the in vitro study, NCI-H292 cells were stimulated with IL-33 in the presence or absence of leptin. Mucin-5AC (MUC5AC) levels were measured using an enzyme-linked immunosorbent assay., Results: Ob/ob mice showed greater Rrs and Ers than wild-type mice. IL-33 with leptin, but not IL-33 alone, enhanced Ers rather than Rrs challenged with methacholine in ob/ob mice, whereas it enhanced Rrs alone in wild-type mice. IL-33-induced eosinophil numbers, cytokine levels in BALF, eosinophilic infiltration around the bronchi, and goblet cell metaplasia were less in ob/ob mice than in wild-type mice. However, leptin pretreatment attenuated these changes in ob/ob mice. MUC5AC levels were increased by co-stimulation with IL-33 and leptin in vitro., Conclusions: Ob/ob mice show innate AHR. IL-33 with leptin, but not IL-33 alone, induces airway inflammation and goblet cell metaplasia and enhances AHR involving peripheral airway closure. This is presumably accelerated by mucus in ob/ob mice. These results may explain some aspects of the pathogenesis of obesity-associated asthma.

Activation of the steroidogenic enzyme CYP11A1 was shown to be necessary for the development of peanut-induced intestinal anaphylaxis and IL-13 production in allergic mice. We determined if levels of CYP11A1 in peripheral blood T cells from peanut-allergic (PA) children compared to non-allergic controls were increased and if levels correlated to IL-13 production and oral challenge outcomes to peanut. CYP11A1 mRNA and protein levels were significantly increased in activated CD4+ T cells from PA patients. In parallel, IL-13 production was significantly increased; IFNγ levels were not different between groups. There were significant correlations between expression levels of CYP11A1 mRNA and levels of IL13 mRNA and protein, levels of serum IgE anti-Ara h 2 and to outcomes of peanut challenge. The importance of CYP11A1 on cytokine production was tested using a CYP11A1 CRISPR/Cas9 KO plasmid or an inhibitor of enzymatic CYP11A1 activity. Inhibition of CYP11A1 activation in patient cells treated with the inhibitor, aminoglutethimide, or CD4+ T cell line transfected with the CYP11A1 KO plasmid resulted in reduced IL-13 production. These data suggest that the CYP11A1-CD4+Tcell-IL-13 axis in activated CD4+ T cells from PA children is associated with development of PA reactions. CYP11A1 may represent a novel target for therapeutic intervention in PA children., Competing Interests: The authors have no conflicts of interest to declare.

Food allergy prevalence is increasing all over the world. Recent epidemiologic studies have shown the link between vitamin D 3 insufficiency and food allergy occurrence. In this study, we investigated the effect of supplementation with cholecalciferol, a widely used form of vitamin D 3 , on food allergy using an experimental mouse model. In wild-type BALB/c mice which were sensitized and challenged with an experimental allergen, ovalbumin, a clinical symptom of food allergy, diarrhea, was significantly induced with the elevation of immunoglobulin E level and the increases of T helper 2 cytokine productions, such as interleukin-4, -5, and -13 (p<0.05), whereas no change in T helper 1 cytokine production, such as interferon-γ, was observed. It was also found that cell population of CD69 + CD4 + T cells was increased slightly in spleen and significantly in the mesenteric lymphnode with the diarrheal symptom (p<0.05). Treatment of cholecalciferol reduced the allergic diarrhea (p<0.05) with the decreasing tendency of CD69 + CD4 + T cells, suggesting that the cell population might be associated with the attenuating effect of cholecalciferol on diarrhea occurrence, although immunoglobulin E levels and cytokine productions were not significantly altered by the treatment of cholecalciferol. When given the mice anti-CD69 mAb treatment, significant improvement of allergic diarrhea symptom was observed (p<0.05), accompanying the decrease of CD69 + CD4 + T cells which suggested the contribution of these cells to the diarrhea symptom. Taken together, we suggest that administration of cholecalciferol might be useful to suppress symptomatic food allergy in association with the decrease of CD69 + CD4 + T cells.

All-trans retinoic acid (ATRA) or mesenchymal stem cells (MSCs) have been shown to promote lung tissue regeneration in animal models of emphysema. However, the reparative effects of the combination of the two and the role of p70S6 kinase-1 (p70S6k1) activation in the repair process have not been defined. Twenty-one days after intratracheal instillation of porcine pancreatic elastase (PPE), MSC and/or 10 days of ATRA treatment was initiated. Thirty-two days later, static lung compliance (Cst), mean linear intercepts (MLIs), and alveolar surface area (S) were measured. After PPE, mice demonstrated increased values of Cst and MLI, and decreased S values. Both ATRA and MSC transfer were individually effective in improving these outcomes while the combination of ATRA and MSCs was even more effective. The combination of p70S6k1 -/- MSCs transfer followed by ATRA demonstrated only modest effects, and rapamycin treatment of recipients with wild-type (WT) MSCs and ATRA failed to show any effect. However, transfer of p70S6k1 over-expressing-MSCs together with ATRA resulted in further improvements over those seen following WT MSCs together with ATRA. ATRA activated p70S6k1 in MSCs in vitro, which was completely inhibited by rapamycin. Tracking of transferred MSCs following ATRA revealed enhanced accumulation and extended survival of MSCs in recipient lungs following PPE but not vehicle instillation. These data suggest that in MSCs, p70S6k1 activation plays a critical role in ATRA-enhanced lung tissue repair, mediated in part by prolonged survival of transferred MSCs. p70S6k1-activated MSCs may represent a novel therapeutic approach to reverse the lung damage seen in emphysema. Stem Cells Translational Medicine 2018;7:551-558., (© 2018 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Mesenchymal stem cells (MSC) exert immune modulatory properties and previous studies demonstrated suppressive effects of MSC treatment in animal models of allergic airway inflammation. However, the underlying mechanisms have not been fully elucidated. We studied the role of MSC in immune activation and subsequent recruitment of monocytes in suppressing airway hyperresponsiveness and airway inflammation using a mouse model of allergic airway inflammation. MSC administration prior to or after allergen challenge inhibited the development of airway inflammation in allergen-sensitized mice. This was accompanied by an influx of CCR2-positive monocytes, which were localized around injected MSC in the lungs. Notably, IL-10-producing monocytes and/or macrophages were also increased in the lungs. Systemic administration of liposomal clodronate or a CCR2 antagonist significantly prevented the suppressive effects of MSC. Activation of MSC by IFN-γ leading to the upregulation of CCL2 expression was essential for the suppressive effects, as administration of wild-type MSC into IFN-γ-deficient recipients, or IFN-γ receptor-deficient or CCL2-deficient MSC into wild-type mice failed to suppress airway inflammation. These results suggest that MSC activation by IFN-γ, followed by increased expression of CCL2 and recruitment of monocytes to the lungs, is essential for suppression by MSC in allergen-induced airway hyperresponsiveness and airway inflammation., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Although diagnostically indispensable, magnetic resonance imaging (MRI) has been, until recently, contraindicated in patients with an implantable cardiac device. MR conditional cardiac devices are now widely used, but the mode programming needed for safe MRI has yet to be established. We reviewed the details of 41 MRI examinations of patients with a MR conditional device. There were no associated adverse events. However, in 3 cases, paced beats competed with the patient's own beats during the MRI examination. We describe 2 of the 3 specific cases because they illustrate these potentially risky situations: a case in which the intrinsic heart rate increased and another in which atrial fibrillation occurred. Safe MRI in patients with an MR conditional device necessitates detailed MRI mode programming. The MRI pacing mode should be carefully and individually selected.

Background: Eosinophils accumulate at the site of allergic inflammation and are critical effector cells in allergic diseases. Recent studies have also suggested a role for eosinophils in the resolution of inflammation., Objective: To determine the role of eosinophils in the resolution phase of the response to repeated allergen challenge., Methods: Eosinophil-deficient (PHIL) and wild-type (WT) littermates were sensitized and challenged to ovalbumin (OVA) 7 or 11 times. Airway inflammation, airway hyperresponsiveness (AHR) to inhaled methacholine, bronchoalveolar lavage (BAL) cytokine levels, and lung histology were monitored. Intracellular cytokine levels in BAL leukocytes were analyzed by flow cytometry. Groups of OVA-sensitized PHIL mice received bone marrow from WT or IL-10(-/-) donors 30 days before the OVA challenge., Results: PHIL and WT mice developed similar levels of AHR and numbers of leukocytes and cytokine levels in BAL fluid after OVA sensitization and 7 airway challenges; no eosinophils were detected in the PHIL mice. Unlike WT mice, sensitized PHIL mice maintained AHR, lung inflammation, and increased levels of IL-4, IL-5, and IL-13 in BAL fluid after 11 challenges whereas IL-10 and TGF-β levels were decreased. Restoration of eosinophil numbers after injection of bone marrow from WT but not IL-10-deficient mice restored levels of IL-10 and TGF-β in BAL fluid as well as suppressed AHR and inflammation. Intracellular staining of BAL leukocytes revealed the capacity of eosinophils to produce IL-10., Conclusions: After repeated allergen challenge, eosinophils appeared not essential for the development of AHR and lung inflammation but contributed to the resolution of AHR and inflammation by producing IL-10., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Defibrillation threshold (DFT) testing is performed routinely in patients undergoing implantable cardioverter-defibrillator (ICD) implantation to verify the ability of the ICD to terminate ventricular fibrillation (VF). However, neither the efficacy nor the safety of DFT testing has been proven; thus, the necessity of such testing is controversial. We conducted a retrospective study of the efficacy of DFT testing, particularly with respect to long-term outcomes of ICD implantation.The study included 150 patients (125 men, 25 women, aged 59.0 ± 17.6 years) who underwent ICD or cardiac resynchronization therapy defibrillator implantation, with (n = 73) or without (n = 77) intraoperative DFT testing, between June 1996 and September 2007. VF was induced by delivery of a T-wave shock, and a 20-25-J shock was then delivered. If the 20-25-J shock failed to terminate VF, 30 J was delivered. We assessed whether undersensed VF events occurred during DFT testing and/or during patient follow-up and checked for any association between undersensing and delayed shock delivery. During DFT testing, fine VF was sensed, and shocks were delivered in a timely manner. Nevertheless, 2 patients in the DFT testing group died from VF within 3 years after device implantation.DFT testing, in comparison to non-DFT testing, appeared to have no influence on the long-term outcomes of our patients, suggesting that DFT testing at the time of ICD implantation is limited.

Glucocorticoid-induced TNFR family-related protein (GITR)-mediated activation of JNK was shown to regulate the suppressive activity of CD4(+)CD25(+) naturally occurring T regulatory cells (nTregs) in wild-type (WT) hosts. In this study, CD4(+)CD25(+) T cells were shown to be capable of becoming pathogenic effector cells in sensitized and challenged CD8(-/-) recipient mice. Only GITR-expressing CD4(+)CD25(+) T cells, but neither GITR knocked-in CD4(+)CD25(-) T cells nor GITR-silenced CD4(+)CD25(+) T cells, enhanced development of lung allergic responses. Inhibition of JNK in WT nTregs or nTregs from GITR(-/-)and JNK2(-/-) mice failed to enhance lung allergic responses in sensitized and challenged CD8(-/-) recipient mice. The failure to enhance responses was associated with increased bronchoalveolar lavage fluid levels of IL-10 and TGF-β and decreased levels of IL-5, IL-6, and IL-13. In contrast, nTregs from JNK1(-/-) mice, similar to WT nTregs, were fully effective in enhancing responses. Thus, GITR stimulation of nTregs and signaling through JNK2, but not JNK1, triggered the loss of regulatory function while concomitantly gaining pathogenic CD4(+) T effector cell function responsible for exacerbating asthma-like immunopathology., (Copyright © 2014 by The American Association of Immunologists, Inc.)

Background: Janus kinases (JAKs) are regulators of signaling through cytokine receptors. The importance of JAK1/3 signaling on TH2 differentiation and development of lung allergic responses has not been investigated., Objective: We sought to examine a selective JAK1/3 inhibitor (R256) on differentiation of TH subsets in vitro and on development of ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) and inflammation in an experimental model of asthma., Methods: A selective JAK1/3 inhibitor was used to assay the importance of this pathway on induction of TH1, TH2, and TH17 differentiation in vitro. In vivo, the effects of inhibiting JAK1/3 signaling were examined by administering the inhibitor during the sensitization or allergen challenge phases in the primary challenge model or just before provocative challenge in the secondary challenge model. Airway inflammation and AHR were examined after the last airway challenge., Results: In vitro, R256 inhibited differentiation of TH2 but not TH1 or TH17 cells, which was associated with downregulation of signal transducer and activator of transcription (STAT) 6 and STAT5 phosphorylation. However, once polarized, TH2 cells were unaffected by the inhibitor. In vivo, R256 administered during the OVA sensitization phase prevented the development of AHR, airway eosinophilia, mucus hypersecretion, and TH2 cytokine production without changes in TH1 and TH17 cytokine levels, indicating that selective blockade of TH2 differentiation was critical. Inhibitor administration after OVA sensitization but during the challenge phases in the primary or secondary challenge models similarly suppressed AHR, airway eosinophilia, and mucus hypersecretion without any reduction in TH2 cytokine production, suggesting the inhibitory effects were downstream of TH2 cytokine receptor signaling pathways., Conclusions: Targeting the TH2-dependent JAK/STAT activation pathway represents a novel therapeutic approach for the treatment of asthma., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: The provirus integration site for Moloney murine leukemia virus (Pim) 1 kinase is an oncogenic serine/threonine kinase implicated in cytokine-induced cell signaling, whereas Runt-related transcription factor (Runx) has been implicated in the regulation of T-cell differentiation. The interaction of Pim1 kinase and Runx3 in the pathogenesis of peanut allergy has not been defined., Objectives: We sought to determine the effects of Pim1 kinase modulation on Runx3 expression and T(H)2 and T(H)17 cell function in an experimental model of peanut allergy., Methods: A Pim1 kinase inhibitor was administered to peanut-sensitized and challenged wild-type and Runx3(+/-) mice. Symptoms, intestinal inflammation, and Pim1 kinase and Runx3 mRNA expression and protein levels were assessed. The effects of Pim1 kinase inhibition on T(H)1, T(H)2, and T(H)17 differentiation in vivo and in vitro were also determined., Results: Peanut sensitization and challenge resulted in accumulation of inflammatory cells and goblet cell metaplasia and increased levels of Pim1 kinase and T(H)2 and T(H)17 cytokine production but decreased levels of Runx3 mRNA and protein in the small intestines of wild-type mice. All of these findings were normalized with Pim1 kinase inhibition. In sensitized and challenged Runx3(+/-) mice, inhibition of Pim1 kinase had less effect on the development of the full spectrum of intestinal allergic responses. In vitro inhibition of Pim1 kinase attenuated T(H)2 and T(H)17 cell differentiation and expansion while maintaining Runx3 expression in T-cell cultures from wild-type mice; these effects were reduced in T-cell cultures from Runx3(+/-) mice., Conclusion: These data support a novel regulatory axis involving Pim1 kinase and Runx3 in the control of food-induced allergic reactions through the regulation of T(H)2 and T(H)17 differentiation., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

The adoptive transfer of OVA-specific Th1 cells into WT mice followed by OVA inhalation induces a significant elevation of airway hyper-responsiveness (AHR) with neutrophilia but not mucus hypersecretion. Here, we demonstrate that the airway inflammation model, pathogenically characterized as severe asthma, was partly mimicked by i.n. administration of IFN-γ. The administration of IFN-γ instead of Th1 cells caused AHR elevation but not neutrophilia, and remarkably induced neurokinin-2 receptor (NK2R) expression along with neurokinin A (NKA) production in the lung. To evaluate whether NKA/NK2R was involved in airway inflammation, we first investigated the role of NKA/NK2R-signaling in airway smooth muscle cells (ASMCs) in vitro. NK2R mRNA expression was significantly augmented in tracheal tube-derived ASMCs of WT mice but not STAT-1(-/-) mice after stimulation with IFN-γ. In addition, methacholine-mediated Ca(2+) influx into the ASMCs was significantly reduced in the presence of NK2R antagonist. Moreover, the NK2R antagonist strongly inhibited IFN-γ-dependent AHR elevation in vivo. Thus, these results demonstrated that IFN-γ directly acts on ASMCs to elevate AHR via the NKA/NK2R-signaling cascade. Our present findings suggested that NK2R-mediated neuro-immuno crosstalk would be a promising target for developing novel drugs in Th1-cell-mediated airway inflammation, including severe asthma., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The long QT syndrome (LQTS) is occasionally complicated by impaired atrioventricular (AV) conduction. This form of LQTS can manifest before birth or during neonatal life, and no previous report has demonstrated LQTS complicated by impaired AV conduction in elderly patient. This case report describes an elderly patient with an acquired form of LQTS who developed ventricular fibrillation that was successfully defibrillated during admission to the hospital. Electrophysiologic study demonstrated that HV interval was 38 milliseconds and QT interval was 635 milliseconds during sinus rhythm cycle length of 1167 milliseconds. 1:1 AV conduction was maintained to a pacing cycle length of 545 milliseconds with an AH interval of 144 milliseconds, HV interval of 44 milliseconds, and right ventricular monophasic action potential duration of 360 milliseconds. However, 2:1 HV block developed at a pacing cycle length of 500 milliseconds. Intravenous administration of mexiletine decreased the cycle length of developing HV block to 360 milliseconds., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The type 1 (coved) ECG pattern is diagnostic for Brugada syndrome; types 2 and 3 require antiarrhythmic drug challenge to confirm its presence. We evaluated a 12-lead ECG-based criterion to differentiate between ordinary incomplete right bundle branch block (iRBBB) and true type 2 and 3 patterns that evolve toward type 1 during drug challenge. The subjects were 22 patients (21 men, 1 woman; mean age, 46.8 ± 13.2 years) referred for drug challenge (1 mg/kg pilsicainide, iv). In magnified ECG lead V1 and/or V2 with an iRBBB pattern, the baseline angle defined as the cross section of the upslope of the r' wave with the downslope of the r' wave was measured and compared between patients responding negatively versus positively to drug challenge, and was found to be significantly smaller in patients responding negatively (20.9 ± 12.9°, n = 6, versus 38.7 ± 16.5°, n = 13; P = 0.009). This ECG-based method successfully discriminates between the ordinary iRBBB pattern and drug-induced evolution toward a type 1 Brugada ECG.

Due to the difficulty in producing a transmural linear lesion and the possibility of complications such as thrombus formation leading to thromboembolism, the catheter-based maze procedure remains problematic. We tested, in pigs, the possibility of using a temperature-controlled cooled-tip radiofrequency (RF) ablation system together with a realtime position management (RPM) system to create a transmural linear lesion uncomplicated by thrombus formation.Nine pigs underwent insertion of two electrode catheters (each with two ultrasound electrodes), one into the coronary sinus (CS) and one into the right ventricular apex (references for ultrasound-based non-fluoroscopic three-dimensional mapping). A cooled-tip catheter (with two ultrasound electrodes) was introduced into the right atrium. Linear right atrial ablation was performed with a custom radiofrequency (RF) generator. The catheter was perfused with 0.66 mL/second of saline. RF was delivered for 60 seconds at a target temperature of 40°C. A linear ablation line was created between the superior vena cava and inferior vena cava. Three-dimensional isochronal maps were created during CS pacing before and after ablation. In 4 of the 9 pigs, a transmural linear ablation line was confirmed by three-dimensional mapping and postmortem macroscopic examination. No endocardial thrombus formation was noted. Temperature-controlled cooled-tip RF linear ablation guided by an RPM system appears to have potential for creating linear lesions in the atria. Further studies are needed to determine whether such an ablation technique and the parameters used will facilitate successful completion of the catheter-based maze procedure.

A 59-year-old man with premature ventricular contractions (PVCs) and slow ventricular tachycardia (VT) underwent electrophysiologic testing. The left ventricular ejection fraction was 27%. Activation mapping showed the site of earliest activation to be the posterolateral site of the right ventricle inflow tract, and we considered this to be the focal mechanism underlying the PVCs/slow VT. Radiofrequency current delivered at this site induced a cluster of rapid ventricular beats (sustained VT) with the same QRS morphology as the PVCs, followed by ventricular fibrillation. The PVC/VT focus might have served as an abnormal automatic trigger and driver for the ventricular fibrillation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: This study was conducted to examine the virtual unipolar electrogram configuration of right/left outflow tract (OT) premature ventricular contraction (PVC)/ventricular tachycardia (VT) origins obtained from a non-contact mapping system (NCMS)., Methods: The subjects consisted of 30 patients with OT-PVCs/VT who underwent NCMS-guided ablation. We evaluated the virtual unipolar electrograms of the origin on 3D right ventricular (RV)-OT isochronal maps., Results: Successful ablation was achieved from the RV in 20 patients (RVOT group), and it failed in 10 (non-RVOT group: including left-sided/pulmonary artery/deep RVOT foci). On the virtual unipolar electrograms, the earliest activation (EA) preceded the QRS onset by 11.2 ± 2.6 ms in the RVOT group and by 7.4 ± 10.5 ms in the non-RVOT group (P = 0.138). The negative slope of the electrogram at the EA site (EA slope(5)), quantified by the virtual unipolar voltage amplitude 5 ms after the EA onset, was significantly steeper in the RVOT group than in the non-RVOT group (0.66 ± 0.52 mV vs. 0.14 ± 0.17 mV, P = 0.005). Cutoff values for the EA-to-QRS onset time and EA slope(5) of ≥ 8 ms and >0.3 mV, respectively, completely differentiated the RVOT group from the non-RVOT group. A lesser EA slope(5) was associated with a greater radiofrequency energy delivery required to terminate RVOT-PVCs/VT., Conclusions: These demonstrate the importance of the virtual unipolar electrograms from OT-PVC/VT origins obtained with the NCMS. The virtual EA predicts both successful and potentially difficult ablation sites from the RV side.

Background: On a cellular level, Brugada syndrome has been attributed to a deep phase 1 notch and subsequent shallow and prolonged repolarization in the right ventricular outflow tract (RVOT). A sodium channel mutation that leads to early inactivation of the late sodium current has been identified in some patients. Thus, drugs that inhibit the transient outward current (I(to)) responsible for the phase 1 notch and/or enhance the late sodium current might suppress arrhythmic events in patients with Brugada syndrome. The effects of quinidine gluconate, a potent inhibitor of I(to), on RVOT action potential duration (APD) restitution kinetics in patients with Brugada syndrome were evaluated., Methods and Results: Programmed ventricular stimulation was performed in 9 Brugada syndrome patients by delivering up to 3 extrastimuli from the right ventricular apex and RVOT. RVOT monophasic action potentials (MAPs) were recorded before and after intravenous administration of quinidine (n=6) or ibutilide (n=3). All patients had inducible ventricular fibrillation (VF) before drug administration. Both quinidine and ibutilide increased steady-state and minimum RVOT MAP duration during programmed stimulation. Quinidine decreased the maximum slope of the RVOT APD restitution curve and VF could not be induced after administration of quinidine in 5 of the 6 patients., Conclusions: Quinidine appears to suppress the induction of VF by increasing RVOT MAP duration and decreasing the maximum slope of the restitution curve.

Brugada syndrome is an inherited disorder that predisposes some patients to sudden cardiac death. It is not well established which Brugada syndrome patients are at risk of life-threatening arrhythmias. We investigated whether standard 12-lead electrocardiograms (ECG) can identify such patients. The subjects were 35 men with Brugada syndrome (mean age, 50.1 ± 12.4 years). Documented ventricular fibrillation or aborted sudden cardiac arrests were judged to be related to the Brugada syndrome. Ten patients (mean age, 49.6 ± 14.9 years) were symptomatic, and 25 (mean age, 50.3 ± 11.5 years) were asymptomatic. We determined the PR interval, QRS duration, and QT interval from baseline 12-lead ECG leads II and V2 as well as the J point elevation amplitude of lead V2. The QRS interval was measured from QRS onset to the J point in leads II and V2. The only significant difference between the symptomatic and asymptomatic patients was the QRS duration measured from lead V2. The mean QRS interval was 129.0 ± 23.9 ms in symptomatic patients versus 108.3 ± 15.9 ms in asymptomatic patients (P = 0.012). A QRS interval in lead V2 ≥ 120 ms was found to be a possible predictor of a life-threatening ventricular arrhythmia and/or syncope (P = 0.012). Prolonged QRS duration as measured on a standard 12-lead ECG is associated with ventricular arrhythmia and could serve as a simple noninvasive marker of vulnerability to life-threatening cardiac events in patients with Brugada syndrome.

The right ventricular outflow tract (RVOT) is considered the arrhythmogenic region that gives rise to Brugada syndrome. To obtain a better understanding of this substrate, we performed electroanatomic mapping of the right ventricle (RV) in patients with Brugada syndrome. The RV was mapped electroanatomically with the CARTO system in 11 patients with asymptomatic Brugada syndrome but in whom ventricular fibrillation was induced by programmed ventricular stimulation, and in 5 control patients. The low voltage zone area (< 1.5 mV) was larger (16.1% versus 7.8%, P < 0.01) and the bipolar electrogram duration was greater (81.6 ± 7.8 ms versus 53.4 ± 5.6 ms, P < 0.01) in the patients with Brugada syndrome versus the control patients; the bipolar electrogram duration was greater in the septal portion and free wall of the RVOT. Our data suggest that regional endocardial conduction slowing based on structural abnormalities exists at the RVOT in Brugada syndrome.

Adoptive cell transfer of an ovalbumin (OVA)-specific T(h)17-polarized cell population from transgenic DO11.10 mice into BALB/c mice followed by OVA inhalation caused airway hyperresponsiveness (AHR) with severe neutrophilia. The transferred T(h)17 cell population-previously polarized in vitro with IL-6, transforming growth factor-beta and IL-23-contained negligible numbers of IFN-gamma-producing cells; however, during T(h)17-cell-dependent airway inflammation, significant numbers of IFN-gamma-producing cells-including cells producing both IL-17 and IFN-gamma and cells producing only IFN-gamma-were detected in the lung in addition to cells producing only IL-17. Using T(h)17-polarized cell populations derived from IL-17(-/-) or IFN-gamma(-/-) mice, it was demonstrated that IL-17 is essential for inducing neutrophilic airway inflammation and that IFN-gamma is required for the AHR elevation. IFN-gamma appeared to be derived from cells producing both IL-17 and IFN-gamma and/or from cells producing only IFN-gamma, which were converted from the transferred T(h)17-polarized cell population. We also found that mAbs that neutralize IL-12 significantly suppressed the conversion of the T(h)17-polarized cell population toward IFN-gamma producers in the lung; concomitantly, with this decreased conversion, IL-12 neutralization also attenuated the AHR elevation in the lung. IL-12-dependent conversion of the transferred T(h)17-polarized cell population into IFN-gamma producers in the lung thus appeared to be a crucial process for inducing AHR elevation in T(h)17-cell-dependent airway inflammation.

Steam pop and intramural charring have been reported during cooled-tip radiofrequency catheter ablation (RFCA). We studied the feasibility of temperature-controlled cooled-tip RFCA in the canine heart.An internally cooled ablation catheter was inserted into the left ventricle. A custom-made radiofrequency (RF) generator capable of controlling the tip-temperature at the preset level by slow increases in the power was used. Temperature-controlled cooled-tip RF applications were performed at a target temperature of 40 degrees C for 90 seconds. Acute study: Intramyocardial temperature was measured at the ablation site in 10 dogs by inserting a fluoroptic probe. Chronic study: Lesion depth and volume were measured in 5 dogs after 3 weeks of survival. In the acute study, no pop or abrupt impedance rise was observed. Maximum intramyocardial temperature was 72.4 + or - 14.4 degrees C at 2-4 mm above the endocardium. No coagulum formation, craters, or intramural charring were observed. Maximum lesion depth was 6.7 + or - 1.5 mm, and lesion volume was 404 + or - 219 mm3. In the chronic study, maximum lesion depth was 5.9 + or - 1.1 mm, and lesion volume was 281 + or - 210 mm(3).Temperature controlled RFCA is feasible with a cooled-tip catheter and an RF generator that slowly increases the RF power until the preset catheter-tip temperature is reached.

Brugada syndrome is often accompanied by atrial tachyarrhythmia, such as atrial fibrillation (AF). The aim of this study was to examine atrial vulnerability in patients with Brugada syndrome. Two groups of patients were compared: 18 patients with Brugada syndrome (Brugada syndrome group) and 11 age-matched patients with neither organic heart disease nor AF episodes (control group). Programmed electrical stimulation was performed from the right atrium (RA), and the effective refractory period of the right atrium (ERP-RA), interatrial conduction time (IACT), monophasic action potentials (MAPs) at the high RA, and the inducibility of AF lasting > 30 seconds were studied. MAP duration at 80% repolarization (MAPD(80)) was calculated. AF was induced with a single extrastimulus or double extrastimuli in all patients with Brugada syndrome but in none of the control patients. The ERP-RA did not differ between the groups. IACT at the shortest diastolic interval was significantly increased in the Brugada syndrome group compared to that in the control group. The maximum slope of the MAPD(80) restitution curve was significantly steeper in the Brugada syndrome group than in the control group (2.4 + or - 2.0 versus 0.82 + or - 0.36, P < 0.02). Ventricular fibrillation was induced with ventricular programmed stimulation in all Brugada syndrome patients. Both abnormal interatrial conduction and steep restitution of action potential duration may contribute to the atrial arrhythmogenicity in Brugada syndrome.

Background: Although patients with Brugada syndrome (BS) are at risk of ventricular fibrillation (VF) and ensuing death, the action potential duration (APD) restitution properties of the right ventricular outflow tract (RVOT) in patients with BS remain undetermined., Methods and Results: Endocardial monophasic action potentials (MAPs) were obtained from 16 patients with BS and 17 control patients. MAPs were recorded from the RVOT in all patients. The MAP duration at 90% repolarization (MAPD(90)), effective refractory period (ERP), and maximum slope of the APD restitution curve were obtained. VF was induced with up to 3 extrastimuli from the RV apex or RVOT. There was no difference in MAPD(90) between the 2 groups, but the ERP was significantly shorter in patients with BS than in control patients (210.7+/-10.5 vs 223.8+/-13.4 ms, P=0.008). MAPD at the shortest diastolic interval was significantly shorter in patients with BS than in control patients (149.9+/-19.9 vs 179.8+/-13.7 ms, P<0.001). The maximum slope of the APD restitution curve was steeper in patients with BS than in control patients (2.90+/-1.29 vs 1.38+/-0.41, P<0.001)., Conclusions: The shorter ERP, shorter MAPD at the shortest diastolic interval and steeply sloped APD restitution curve in the RVOT appear to be related to the inducibility of VF in patients with BS.

Sustained atrial fibrillation (AF) was induced by atrial burst pacing, and monophasic action potentials (MAPs) were recorded. MAP alternans was observed at a cycle length (CL) of 167.5 ± 28.2 msec before burst pacing and 201.3 ± 40.2 msec after burst pacing. AF > 5 minutes duration was induced in 1 dog in the control condition but in all 8 dogs after burst pacing. The difference in RA MAPD(80) of the first spontaneous beat and steady-state sinus rhythm was significantly larger after atrial burst pacing than before atrial burst pacing (31.5 ± 15.9 msec versus 8.2 ± 9.0 msec) In 4 dogs, late phase 3 early after depolarization was observed after rapid atrial pacing. Rapid atrial pacing-induced electrical remodeling includes APD alternans during rapid atrial pacing and also causes an increase in the MAPD of the initial several beats and the development of late phase 3 early afterdepolarizations after a sudden increase in CL.

A 46-year-old man with type II Brugada electrocardiogram pattern changed to a type I Brugada type electrocardiogram pattern by class I antiarrhythmic drug (pilsicainide) underwent electrophysiologic study. Ventricular fibrillation was induced by double extrastimuli from the right ventricular (RV) apex. Monophasic action potentials (MAPs) were then recorded from the high right atrium. Duration of MAP at a coupling interval of 220 milliseconds was 122 milliseconds, and local activation of S2 spread to the left atrium. However, MAP at a coupling interval of 210 milliseconds was 112 milliseconds, and local activation of S2 failed to spread to the rest of atrium.

The reported pathogenesis of Brugada syndrome is phase 2 reentry resulting from shortening of the epicardial action potential duration at the right ventricular outflow tract (RVOT). However, several studies have revealed a high incidence of ventricular late potentials and high rate of ventricular fibrillation (VF) induced by programmed ventricular stimulation (PVS). The aim of the present study was to evaluate the role of slow conduction at the RVOT for the initiation of VF by PVS and any underlying pathological conditions in Brugada syndrome. Endocardial mapping of the RVOT and endomyocardial biopsy of the right ventricle were performed in 25 patients with Brugada syndrome with inducible VF. Late potentials were positive in 11 of the 25 (44%) patients. Low-amplitude fragmented and delayed electrograms were recorded at the RVOT in 13 of 18 (72.2%) patients. Histologic examination of the biopsy samples revealed fatty tissue infiltration, interstitial fibrosis, lymphocyte infiltration, and/or myocyte disorganization in 13 patients. Slow conduction at the RVOT may contribute to the induction of VF by PVS in Brugada syndrome. Various pathomorphologic changes may contribute to slow conduction at the RVOT.

This case report describes a left bundle branch block (LBBB)-type ventricular tachycardia (VT) with a unique reentrant circuit in a patient with cardiac sarcoidosis. The VT morphology and pace mapping supported an exit site of the VT from the basal posterior right ventricle (RV) septum. Nonetheless, concealed entrainment was established by pacing from a septal left ventricular (LV) site recording a diastolic potential, opposite site to the RV site. A point ablation at that LV site could successfully terminate the VT, suggesting that a critical isthmus was located on the LV side of the interventricular septum despite the demonstration of an LBBB-type VT.

Background: The efficacy of transcatheter cryoablation for ventricular tachycardia (VT) remains controversial because of the limited size of the lesion produced. An increased lesion size if the cryoablation catheter profile and catheter tip length were increased was hypothesized., Methods and Results: Closed-chest transcatheter cryoablation was applied with 7F, 6-mm tip (n=11, 7F group) and 9F, 8-mm tip (n=8, 9F group) catheters to the left ventricular (LV) endocardium and epicardium. Catheter-tip temperature was set to -70 to -80 degrees C, and cryoablation duration was set to 240 s. In acute experiments in the 7F group, endocardial lesion volume was 144.1 +/-86.0 mm(3) and lesion depth was 5.1 +/-1.6 mm, and epicardial lesion volume was 205.6 +/-157.8 mm(3) and lesion depth was 4.7 +/-2.2 mm. In the 9F group, endocardial lesion volume was 301.5 +/-177.4 mm(3) (P<0.001 vs 7F group) and lesion depth was 8.4 +/-1.9 mm (P<0.001 vs 7F group), and epicardial lesion volume was 375.3 +/-167.6 mm(3) (P<0.01 vs 7F group) and lesion depth was 5.0 +/-2.3 mm., Conclusions: Transcatheter cryoablation of the LV endocardium and epicardium using a larger profile and longer tip electrode may be useful for treating VT originating from the midmyocardium or epicardium.

3-Methylcholanthrene (MCA)-induced sarcomas have been used as conventional tools for investigating immunosurveillance against tumor development. However, MCA-induced sarcoma is not always an ideal model for the study of the human cancer system because carcinomas and not sarcomas are the dominant types of human cancers. To resolve this problem, we established a novel and simple method to induce mouse squamous cell carcinomas (SCCs). As well known, the subcutaneous injection of MCA caused the formation of sarcomas at 100% incidence. However, we here first succeeded at inducing SCC at 60% of incidence within 2 months by a single intra-dermal injection of MCA. Using this primary SCC model, we demonstrated the critical role of interferon (IFN)-gamma-dependent type 1 immunity in immunosurveillance against SCC from the following results: (i) The incidence of SCC was accelerated in IFN-gamma-deficient mice compared with that in wild-type mice; (ii) In vivo injection of CpG-oligodeoxynucleotides (CpG-ODN) caused a marked reduction in the incidence of SCC in parallel with the activation of type 1-dependent antitumor immunity and (iii) The antitumor activity of CpG-ODN was significantly decreased in IFN-gamma-deficient mice. Thus, our established MCA-induced mouse SCC model could be a powerful tool for evaluating immunosurveillance mechanisms during the development of SCC and might result in a novel strategy to address immunosurveillance mechanisms of human cancer.

This study was designed to evaluate whether the right ventricular outflow tract (RVOT) is the arrhythmogenic focus in Brugada syndrome. We enrolled 45 patients with Brugada-type ECG who underwent programmed ventricular stimulation and inducible ventricular fibrillation (VF). In 25 of these 32 patients, repetitive VT was observed before degeneration into VF. The QRS morphology of surface ECG and intracardiac electrograms were evaluated to determine the origin of the ventricular tachycardia (VT) that degenerated into VF. The VT morphology was a left bundle branch block pattern with an inferior axis in 22 of 28 VTs and the intracardiac conduction sequence during VT revealed activation from the RVOT to the RV apex in these 22 VTs. The majority of the patients with Brugada syndrome showed repetitive VT originating from the RVOT that degenerated into VF. The RVOT may be an arrhythmogenic focus in patients with Brugada syndrome.

Unmethylated cytosine-phosphorothioate-guanine containing oligodeoxynucleotides (CpG-ODN) is known as a ligand of toll-like receptor 9 (TLR9), which selectively activates type-1 immunity. We have already reported that the vaccination of tumor-bearing mice with liposome-CpG coencapsulated with model-tumor antigen, ovalbumin (OVA) (CpG + OVA-liposome) caused complete cure of the mice bearing OVA-expressing EG-7 lymphoma cells. However, the same therapy was not effective to eradicate Lewis lung carcinoma (LLC)-OVA-carcinoma. To overcome the refractoriness of LLC-OVA, we tried the combination therapy of radiation with CpG-based tumor vaccination. When LLC-OVA-carcinoma intradermally (i.d.) injected into C57BL/6 became palpable (7-8 mm), the mice were irradiated twice with a dose of 14 Gy at intervals of 24 h. After the second radiation, CpG + OVA-liposome was i.d. administered near the draining lymph node (DLN) of the tumor mass. The tumor growth of mice treated with radiation plus CpG + OVA-liposome was greatly inhibited and approximately 60% of mice treated were completely cured. Moreover, the combined therapy with radiation and CpG + OVA-liposome allowed the augmented induction of OVA-tetramer(+) LLC-OVA-specific cytotoxic T lymphocyte (CTL) in DLN of tumor-bearing mice. These results indicate that the combined therapy of radiation with CpG-based tumor vaccine is a useful strategy to eradicate intractable carcinoma.

Ablation catheters with multiple electrodes are effective for the creation of linear atrial lesions but are associated with an increased risk of coagulum formation. In an animal study, we used a novel 9Fr deflectable ablation catheter with two saline/foam electrode pocket covered with 20 mm tubing. Each pocket contained six 2-mm long electrodes with a 1-mm interelectrode distance. Bipolar electrograms between the 3 distal and 3 proximal composite electrodes were recorded, and the pacing threshold was determined before and after radiofrequency (RF) ablation. Long linear lesions were created by applying RF energy for 90 seconds at 50 W during saline irrigation (0.4 mL/sec) between 1) the superior vena cava (SVC) and inferior vena cava (IVC), 2) SVC, fossa ovalis, and IVC, 3) transverse loop from the crista terminalis to the tricuspid valve (TV), and 4) TV and the IVC. Continuous transmural lesions were created only in a minority of cases, and lesion gaps were noted in the free wall lesions. No coagulum formation was observed after RF energy delivery. A long lesion can be created in the right atrium by using an irrigated balloon catheter, but continuous lesion formation was achieved only in a minority of animals.

A 71-year-old man with frequent ventricular premature contractions after right hip joint surgery was referred to the Cardiology Division. Twelve-lead ECG showed type II Brugada-type ECG and signal-averaged ECG showed positive ventricular late potentials. The 12-lead ECG changed to type I Brugada-type after administration of the class Ic antiarrhythmic drug, pilsicainide. Ventricular fibrillation (VF) was reproducibly induced with double premature stimuli from the right ventricular outflow tract (RVOT) at a basic cycle length (BCL) of 400 ms. Monophasic action potentials (MAPs) recorded from the RVOT at a BCL of 400 ms showed MAP alternans and VF was only induced when extrastimuli were applied after a shorter MAP of the alternans.

This study was designed to determine whether endocardial high-frequency stimulation at the pulmonary vein (PV) antrums can localize cardiac autonomic ganglionated plexi (GP) and whether ablation at these sites can evoke a vagal response and provide a long-term benefit after PV isolation (PVI) for atrial fibrillation (AF). Radiofrequency ablation of each PV antrum was performed in 21 patients with paroxysmal AF (n = 17) or persistent (n = 4) AF. In 8 patients with paroxysmal AF, a ring electrode catheter was placed at each PV antrum. High-frequency stimulation prolonged the R-R interval in 6 of 8 patients at the left superior (LS) PV, in 3 of 8 patients at the left inferior (LI) PV, in 3 of 8 patients at the right superior (RS) PV, and in 3 of 8 patients at the right inferior (RI) PV. A decrease in sinus rate > 20% was observed in 4 of 21 patients during LS PVI, in 2 of 21 patients during RS PVI, and in 1 of 2 patients during RI PVI. Atrioventricular block or a > 5 second pause was observed in 5 of 21 patients during LS PVI. AF recurred during the follow-up period in 5 of the 16 patients (31%) who had no atrioventricular block or > 5 second pause during PVI but did not recur in 5 patients in whom atrioventricular block or a > 5 second pause developed during PVI. GP can be identified by endocardial stimulation. The AF recurrence rate is decreased when a vagal response is achieved by radiofrequency ablation.

A 44-year-old man who had suffered multiple episodes of syncope presented with ventricular fibrillation (VF). Structural heart disease was ruled out. Programmed stimulation induced VF at the right ventricular apex (RVA) but not at the outflow tract (RVOT). Monophasic action potential duration (MAPD) at a basic cycle length of 400 msec was shorter at the RVA than at the RVOT (208 versus 231 ms). The maximum slope of the MAPD restitution curve at the 400-msec cycle length was much steeper at the RVA than at the RVOT (1.4 versus 1.0). Such spatial heterogeneity of the MAPD and of its restitution may facilitate wavebreak and functional reentry, predisposing to VF.

Background: It was hypothesized that atrial premature contractions (APCs) originating in the pulmonary veins (PVs) or superior vena cava (SVC) can be localized by evaluating characteristics of the P wave., Methods and Results: Thirty-eight patients with paroxysmal atrial fibrillation were studied. P wave polarity and morphology of the ECGs during pacing from PVs were analyzed and compared to those of APCs originating from PVs. The P wave angle and notch in lead II during pacing from the right superior (RS) PV and SVC was compared to those of spontaneous APCs originating from those veins. A positive P wave in lead I was helpful in predicting right PV origin. A positive P wave in lead II distinguished superior PV origin. A notched P wave was helpful in predicting left PV origin. P wave polarity in lead II was positive during RSPV and SVC pacing. P waves in lead II during RSPV pacing had notching in 80%, but all P waves were smooth during SVC pacing. A P wave angle of > 40 degrees and notching in lead II showed RSPV origin., Conclusions: These criteria are helpful in selecting which of the 4 PVs should be isolated when APCs cannot be recorded after transseptal puncture.

Background: High-speed rotational coronary venous (CV) angiography (RCVA) permits dynamic, multi-angle visualization of the CV anatomy., Methods and Results: RCVA uses a rapid isocentric rotation over a 108 degrees arc, right anterior oblique (RAO) 54 degrees to left anterior oblique (LAO) 54 degrees, in 4 s. Three-dimensional models of the venous tree were reconstructed, and the rotational images were analyzed using a full range of gantry angles, providing the operator with considerably more information about the CV anatomy than standard coronary sinus angiography images (SCVA)., Conclusions: The SCVA view, which optimally displayed the appropriate coronary sinus branch for left ventricular lead implantation, was often different from the conventional RAO and LAO views.

Background: It remains unknown why atrial flutter (AFL) occurs as either a chronic or paroxysmal arrhythmia., Purpose: The aim of the study was to compare intracardiac echocardiographic (ICE) images of the crista terminalis (CT) and transverse conduction properties of the CT between chronic and paroxysmal forms of common AFL., Methods: Chronic AFL (n = 7) was defined as non-self-terminating AFL lasting >1 month, and paroxysmal AFL (n = 8) was defined as an intermittent arrhythmia with symptomatic episodes of 24 hours maximum duration. ICE images of the right atrium were recorded with a 9 F 9-MHz intracardiac ultrasound catheter during pullback at 0.5-mm intervals from the superior vena cava to the inferior vena cava triggered by electrocardiogram and respiration. The two-dimensional image of the right atrium was reconstructed into a three-dimensional (3-D) image., Results: Three-dimensional images from patients with chronic AFL showed the CT to be thick and continuous, and conduction across the CT was blocked at a pacing rate just above sinus rhythm in all seven patients. In contrast, 3D images from paroxysmal AFL showed the CT to be thin and discontinuous, and conduction across the CT during midseptal pacing was observed in five of the eight patients., Conclusion: The nature of AFL is determined, at least in part, by anatomic and electrophysiologic characteristics of the CT.