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Abstract Background The Mt FUJI study was a multicenter, prospective, randomized, single‐blind, controlled trial comparing delivery catheter‐based and stylet‐based right ventricular (RV) lead placement at the RV septum. This study extended the follow‐up duration to 1 year after implantation. Methods Seventy patients with pacemaker indications for atrioventricular block were randomly assigned to the delivery catheter and stylet groups. We compared the mid‐term efficacy and safety between the two groups at 1 year after implantation. The primary outcome was the change in the left ventricular ejection fraction (LVEF), and the secondary outcomes were changes in brain natriuretic peptide (BNP) levels, lead parameters, paced QRS duration, and the incidence of adverse events. Results At the 1‐year follow‐up, no significant differences were observed in the changes in the LVEF (+1.0% ± 8.6% vs. +3.1% ± 8.1%, p = .332), BNP levels (+8.0 [−11.1, 26.5] pg/mL vs. −8.7 [−15.3, 13.2] pg/mL, p = .193), or lead performance between the delivery catheter and stylet groups. The QRS duration was significantly shorter in the delivery catheter group than in the stylet group (128 ± 23 ms vs. 146 ± 17 ms, p

Abstract Background Despite advances in the treatment of cancer, pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to the lack of effective therapies. Our previous study showed that Luteolin (Lut), a flavonoid, suppressed pancreatocarcinogenesis and reduced the expression of dihydropyrimidine dehydrogenase (DPYD), an enzyme that degrades pyrimidines such as 5‐fluorouracil (5‐FU), in PDACs. In this study, we investigated the role of DPYD and evaluated the therapeutic potential of combining 5‐FU with Lut in PDACs. Methods and Results PDAC cells overexpressing DPYD showed increased proliferation, and invasiveness, adding to the resistance to 5‐FU. The xenograft tumors of DPYD‐overexpressing PDAC cells also exhibit enhanced growth and invasion compared to the control xenograft tumors. RNA‐seq analysis of the DPYD‐overexpressing PDAC xenograft tumors revealed an upregulation of genes associated with metallopeptidase activity—MMP9 and MEP1A. Furthermore, the overexpression of MEP1A in PDAC was associated with invasion. Next, we investigated the combined effects of Lut, a DPYD suppressor, and 5‐FU on DPYD‐overexpressing xenograft tumors and PDAC of Pdx1‐Cre; LSL‐KrasG12D/+; Trp53flox/flox(KPPC) mice. Neither single administration of 5‐FU nor Lut showed significant inhibitory effects; however, the combined administration of 5‐FU and Lut exhibited a significant tumor‐suppressive effect in both the xenograft tumors and KPPC models. Conclusion We have elucidated that DPYD expression contributes to proliferation, invasiveness, and 5‐FU resistance, in PDACs. The combination therapy of Lut and 5‐FU holds the potential for enhanced efficacy against PDACs.

Abstract Background The lesion index (LSI) has been used to estimate lesion formation after radiofrequency catheter ablation. However, the impedance drop and decrease in bipolar amplitude of intracardiac electrograms, which are parameters that are traditionally used to predict effective ablation lesions, are not used to calculate LSI. Therefore, we aimed to investigate the association between LSI and traditional parameters. Methods We retrospectively investigated 1355 ablation points from 31 patients who underwent LSI‐guided pulmonary vein isolation (PVI) using TactiCath. All points were classified into 3 groups based on the impedance drop: (i) 20 Ω (n = 379). The LSI targets were 4.5 for the posterior left atrium and 5.2 for the anterior left atrium. After excluding 583 points at which it was difficult to measure the amplitude, 772 ablation points during sinus rhythm were included in the analysis of bipolar amplitude. Results The target LSI was achieved at 1177 points (86.9%). The median total impedance drop and amplitude just after ablation were 16.0 [13.0–20.0] Ω and 0.21 [0.14–0.30] mV, respectively. There were significant differences among the 3 groups in the impedance and amplitude before ablation, power, target LSI, final LSI, contact force, and interlesion distance. An impedance drop of >10 Ω or an amplitude reduction of >50% was achieved at 95% and 82% of the study points, respectively. There were no major complications at any of the ablation points. Conclusion LSI‐guided PVI seemed to be useful for making sufficient ablation lesions, as assessed by the conventional parameters of impedance and amplitude change.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease known for its dense tumor stroma. Focal adhesion kinase inhibitor (FAKi), a non-receptor type tyrosine kinase inhibitor, reduces the tumor stroma. G47Δ, a third-generation oncolytic herpes simplex virus type 1, destroys tumor cells selectively and induces antitumor immune responses. This study evaluates the efficacy of FAKi and G47Δ in PDAC models in combination with or without immune checkpoint inhibitors. G47Δ was effective in human PDAC cell lines in vitro and in subcutaneous as well as orthotopic tumor models. Transgenic mouse-derived #146 cells were used to generate subcutaneous PDAC tumors with rich stroma in immunocompetent mice. In this #146 tumor model, the efficacy of FAKi was synergistically augmented when combined with G47Δ, which reflected not only a decreased stromal content but also a significant shifting of the tumor microenvironment toward immune stimulation. In transgenic autochthonous PKF mice, a rare model that develops stroma-rich PDAC with a 100% penetrance and resembles human PDAC in various aspects, the prolongation of survival compared with FAKi alone was achieved only when FAKi was combined with G47Δ and immune checkpoint inhibitors. The FAKi combination therapy may be useful to overcome the treatment resistance of stroma-rich PDAC.

Abstract Background Pulmonary vein stenosis (PVS) is a severe complication of atrial fibrillation (AF) ablation resulting in narrowing of affected pulmonary veins (PVs). Interventional treatment consists of angioplasty with or without PV stenting. The optimal postprocedural antithrombotic therapy is not known. Study aims To investigate the impact of antithrombotic medical therapy on recurrence of PVS after PV angioplasty. Methods A retrospective study of patients undergoing PV angioplasty with or without stent implantation in two German centers was performed. Postinterventional antithrombotic therapy consisted of either dual antiplatelet therapy (DAPT) or a combination of oral anticoagulation with single or dual antiplatelet therapy for 3–12 months after intervention. Angiographic follow‐up was recommended 3, 6, and 12 months after intervention and in case of symptom recurrence. Results Thirty patients underwent treatment of 42 PVS. After intervention, twenty‐eight patients received triple therapy and 14 patients received dual therapy/DAPT; restenosis occurred in 5/22 (22.7%) patients with triple therapy and 8/14 (57.1%) patients with dual therapy/DAPT PV (p = .001). Estimated freedom from PV restenosis after 500 days was 18.8 ± 15.8% (dual therapy/DAPT) and 76.2 ± 10.5% (triple therapy) (p = .003). Univariate regression analysis revealed postprocedural medication as a significant risk factor for restenosis (p = .019). No bleeding events occurred regardless of applied antithrombotic therapy. Conclusion Triple antithrombotic therapy after PV angioplasty is associated with less frequent restenosis as compared to dual antiplatelet therapy or a combination of anticoagulation and single antiplatelet therapy. No severe bleeding events occurred in patients on triple therapy. These findings need to be confirmed in larger patient cohorts.

Background: Malnutrition in cardiovascular disease is associated with poor prognosis, especially in patients with heart failure and acute coronary syndrome (ACS). High bleeding risk is also linked to coronary artery disease prognosis, including ACS. However, whether the extent of malnutrition and high bleeding risk have a cumulative impact on the long-term prognosis of patients with ACS who undergo percutaneous coronary intervention remains unclear. Methods: We analyzed 275 patients with ACS treated with percutaneous coronary intervention. The Controlling Nutritional Status score and Japanese version of the Academic Research Consortium for High Bleeding Risk criteria (J-HBR) were retrospectively evaluated. The primary and secondary outcomes were adjusted using the inverse probability treatment weighting method. Results: The prevalence of moderate or severe malnutrition in this cohort was 16%. Kaplan–Meier analysis showed a significantly higher incidence of major adverse cardiovascular and cerebrovascular events in patients who were moderately or severely malnourished than in those who were not. Notably, the incidence of these major events was similar between severely malnourished patients with J-HBR and those without. Conclusion: Moderate or severe malnutrition has a significant impact on the long-term prognosis of patients with ACS who undergo percutaneous coronary intervention.

Abstract Aims To evaluate outcomes of percutaneous left atrial appendage closure (LAAC) in patients with congestive heart failure (CHF) and non‐valvular atrial fibrillation (AF) in a consecutive, industry‐independent registry associated with periprocedural success and complications during long‐term follow‐up. Methods and results For this analysis, we included patients who underwent transcatheter LAAC from January 2014 to December 2019 at the University Heart Center in Lübeck, Germany, and compared patients with presence of CHF defined as patients with a reduced left ventricular ejection fraction (LVEF ≤ 40%), patients with a mid‐range LVEF (LVEF 41–49%), patients with diastolic dysfunction and preserved LVEF (LVEF ≥ 50%), and patients with right‐sided heart failure and impaired right ventricular function (tricuspid annular plane systolic excursion

This paper presents a compact six-port power divider with simple structure that performs two independent out-of-phase divisions. The proposed power divider consists of a uniplanar ring crossover with four transmission lines for output and two feeding lines. The $S$ -parameter matrix of the proposed power divider is derived analytically, and it is shown that the two independent out-of-phase divisions are realized when the circumferential length of the ring is one guided wavelength $\lambda _{g}$ whereas conventional power dividers require a $2\lambda _{g}$ or $2.5\lambda _{g}$ ring. Two power dividers configured with striplines were designed to have −10-dB impedance bandwidths of 5% and 10% with a center frequency of 2.45GHz. The designed power dividers were fabricated and two independent out-of-phase divisions having small amplitude imbalance were verified by measurements. Because of its compactness, the proposed power divider might be applied to the feeding network of dual-feed dual-polarized array antennas with narrow element spacing.

Objective We sought to investigate whether it is possible to obtain individualised left anterior oblique (LAO) by preprocedural electrocardiographic parameters and, if so, whether these parameters can help to improve the success rate of right ventricular (RV) lead implantation into the interventricular septum.Methods In this observational study, we assessed the relationship between preoperative electrocardiographic parameters and the angle of the interventricular septum obtained using thoracic CT. The participants were divided into two groups: a retrospective derivation cohort to derive the optimal formula for the individual septum axis, and a prospective internal validation cohort to which we applied the optimal formula and implanted using the new method.Results In the retrospective derivation cohort (n=39), the mean angle of individualised LAO assessed by thoracic CT was 53.1°±8.9°, and the preoperative ECG QRS axis was strongly correlated with the interventricular septum axis (R2=0.490). LAO projection derived from the preoperative ECG QRS axis confirmed that the RV lead was placed in the interventricular septum during the pacemaker procedure in the prospective internal validation group (n=30). The success rate for placing the RV lead into the interventricular septum was significantly improved in the internal validation cohort (93% vs 64%, p

Background: The guideline-recommended low-density lipoprotein cholesterol target level of p = 0.498). The two groups showed no significant differences in hospitalization for worsening heart failure and adverse events. Conclusions: In ACS patients who underwent PCI, short-term PCSK9 antibody therapy with conventional LLT was feasible in this pilot clinical trial. Long-term follow-up in a larger scale clinical trial is warranted.

Pulmonary vein isolation has become a cornerstone treatment for catheter ablation of atrial fibrillation (AF). Recent reports show that additional ablation targeting low-voltage zones reduces AF recurrence. However, the pre-procedural predictors of low-voltage zones remain elusive. We retrospectively enrolled 359 patients (mean age 63.7 ± 10.8 years; 73 females; and 149 had persistent atrial fibrillation) who underwent catheter ablation for AF and left atrial (LA) voltage mapping during sinus rhythm or atrial pacing. Low-voltage zones were defined as area of > 5 cm2 with a bipolar electrogram amplitude of < 0.50 mV. Overall, 51 (14.2%) patients had low-voltage zones. Patients with low-voltage zones were older (67.9 ± 9.9 vs. 63.0 ± 10.8 years; P = 0.003), predominantly female (33.3% vs. 18.2%; P = 0.013), had higher prevalence of dilated cardiomyopathy (DCM) (11.8% vs. 1.6%; P = 0.002) and hypertrophic cardiomyopathy (HCM) (9.8% vs. 2.6%; P = 0.025), and had larger LA volumes (153.6 ± 46.4 vs. 117.7 ± 67.8 mL; P < 0.001) than those without low-voltage zones. Multivariate logistic regression analysis revealed that age (OR 1.060; 95% CI 1.022–1.101, P = 0.002), female sex (OR 2.978; 95% CI 1.340–6.615, P = 0.007), DCM (OR 8.341; 95% CI 1.381–50.372, P = 0.021), HCM (OR 5.044; 95% CI 1.314–19.363, P = 0.018), persistent AF (OR 4.188; 95% CI 1.928–9.100, P < 0.001), and larger LA volume (OR 3.215; 95% CI 1.378–7.502, P = 0.007) were independently associated with the presence of low-voltage zones. Patient age, female sex, DCM, HCM, persistent AF and larger LA volume may predict the presence of low-voltage zones and could be useful in selecting the appropriate ablation strategy for AF.

Background: Atrial fibrillation (AF) ablation is performed under deep sedation, which may cause inspiration-induced negative left atrial pressure (INLAP) associated with deep inspiration. INLAP could be the cause of periprocedural complications. Methods: We retrospectively enrolled 381 patients with AF (mean age, 63.9 ± 10.8 years; 76 women; 216 cases of paroxysmal AF) who underwent CA under deep sedation using an adaptive servo ventilator (ASV). Patients whose LAP was not obtained were excluded. INLAP was defined as 2DS2-Vasc scores (2.3 ± 1.5 vs. 2.1 ± 1.6) and 3% oxygen desaturation indexes (median 18.6 (interquartile range 11.2–31.1) vs. 15.7 (8.1–25.3)), and higher prevalence of diabetes mellitus (23.3 vs. 13.3%) than patients without INLAP. Air embolism occurred in four patients with INLAP (3.0 vs. 0.0%). Conclusion: INLAP is not rare in patients undergoing CA for AF under deep sedation with ASV. Much attention should be paid to the possibility of air embolism in patients with INLAP.

Background: Data reporting a head-to-head comparison between Amulet and Watchman devices are scarce. The aim of this study was to compare the Watchman™ versus Amulet™ left atrial appendage closure (LAAC) devices in a consecutive, industry-independent registry. Methods: Patients who underwent LAAC using Watchman or Amulet devices from January 2014 to December 2019 at the University Heart Center Lübeck, Lübeck, Germany were included in the present analysis. Primary endpoints included periprocedural complications (in-hospital death, pericardial tamponade, device embolization, stroke, major bleeding and vascular access complications), and complications during long-term follow-up (ischemic stroke, hemorrhagic stroke, thromboembolism, device thrombus, bleeding and death). Results: After matching the patients for age (±5 years), gender, CHA2DS2Vasc score (±1) and HASBLED score (±1), each of the Watchman and the Amulet groups included 113 patients. Patients in the Amulet group had significantly more periprocedural complications (2.7% vs 10.6%, p = 0.029; respectively) and more major bleeding complications (0% vs 5.3%, p = 0.029; respectively). During long-term follow-up, the rate of events was comparable between the Watchman and Amulet groups (18.3% versus 20.8%, p = 0.729; respectively). Conclusion: Amulet LAAC device was associated with increased periprocedural complications as compared to Watchman LAAC device. On long-term follow-up, both devices showed comparable efficacy and safety.

Background: Catheter ablation for atrial fibrillation (AF) treatment provides effective and durable pulmonary vein isolation (PVI) and is associated with encouraging clinical outcome. A novel CF sensing temperature-controlled radiofrequency (RF) ablation catheter allows for very high-power short-duration (vHP-SD, 90 W/4 s) ablation aiming a potentially safer, more effective and faster ablation. We thought to evaluate preliminary safety and efficacy of vHP-SD ablation for PVI utilizing a novel vHP-SD catheter. The data was compared to conventional power-controlled ablation index (AI) guided PVI utilizing conventional contact force (CF) sensing catheters. Methods and Results: Fifty-six patients with paroxysmal or persistent AF were prospectively enrolled in this study. Twenty-eight consecutive patients underwent vHP-SD based PVI (vHP-SD group) and were compared to 28 consecutive patients treated with conventional CF-sensing catheters utilizing the AI (control group). All PVs were successfully isolated using vHP-SD. The median RF ablation time for vHP-SD was 338 (IQR 286, 367) seconds vs control 1580 (IQR 1350, 1848) seconds (p

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high invasive and metastatic potential. We generated a spontaneous PDAC mouse model and examined the therapeutic potential of indirubin 3′-oxime (Indox) against PDAC bearing mouse in vivo. METHODS: Randomized 3-month-old LSL-KrasG12D/+;Trp53flox/+;Pdx-1-cre (KPCflox) mice were intraperitoneally injected with 40 mg/kg Indox (n = 9) or a vehicle (n = 10) twice a week. At the end point, tumor status including proliferation, direct invasion, and distant metastasis was analyzed histopathologically. The inhibitory potentials of Indox for proliferation, migration/invasion, and the phosphorylation of target molecules were determined in KPCflox-derived PDAC cells in vitro. RESULTS: Prolonged survival by Indox via intraperitoneal administration was observed in the KPCflox mice. Indox inhibited tumor proliferation accompanied with low levels of nuclear phosphorylated cyclin-dependent kinase (p-CDK) and cyclin B1 in vivo. Furthermore, Indox inhibited the migration/invasive activities of PDAC via down-regulation of matrix metalloproteinase (MMP)-9 in vitro and in vivo. Antibody array and immunoblotting analysis revealed that Indox inhibited the phosphorylation of multiple molecules, including key upstream proteins of MMP-9 in RAF/extracellular signal-regulated kinase (ERK), AKT, and stress-activated protein kinase/c-Jun-N-terminal kinase (SAPK/JNK) pathways. CONCLUSION: Indox inhibited the proliferative, invasive, and metastatic potentials of PDAC in vitro and in vivo. Therefore, Indox could a therapeutic candidate for treating spontaneously occurring PDAC via blocking the RAF/ERK, AKT and SAPK/JNK pathways.

Introduction Pacing-induced cardiomyopathy occasionally occurs in patients undergoing pacemaker implantation. Although compared with right ventricular (RV) apical pacing, RV septal pacing can attenuate left ventricular dyssynchrony; the success rate of lead placement on the RV septum using the stylet system is low. Additionally, no randomised controlled trial has addressed the issue regarding the accuracy of RV lead placement on the RV septum using the stylet and delivery catheter systems. This study hypothesises that a newly available delivery catheter system can improve the accuracy of RV lead placement on the RV septum.Methods and analysis In a multicentre, prospective, randomised, single-blind, controlled trial, 70 patients with pacemaker indication owing to atrioventricular block will be randomised to either the delivery catheter or stylet group before the pacemaker implantation procedure. The position of the RV lead tip will be assessed using ECG-gated cardiac CT in all patients within 4 weeks after pacemaker implantation. Lead tip positions are classified into three groups: (1) RV septum, (2) anterior/posterior edge of the RV septal wall and (3) RV free wall. The primary endpoint will be the success rate of RV lead tip placement on the RV septum, which will be evaluated using cardiac CT.Ethics and dissemination This study will be conducted according to the stipulations of the Helsinki Declaration and the institutional review board of Hamamatsu University School of Medicine. The results of the study will be disseminated at several research conferences and will be published in peer-reviewed journals.Trial registration number jRCTs042200014; Pre-results.

A 78-year-old male was admitted to our hospital due to frequent palpitation. His electrocardiogram (ECG) presented regular narrow QRS tachycardia with 170 bpm, and catheter ablation was planned. During electroanatomical mapping of the right atrium (RA) with a multiloop mapping catheter, the catheter head was entrapped nearby the ostium of inferior vena cava. Rotation and traction of the catheter failed to detach the catheter head from the RA wall. Exfoliation of connective tissue twined around catheter tip by forceps, which were designed for endomyocardial biopsy, succeeded to retract and remove the catheter. Postprocedural echocardiography and pathologic examination proved the existence of Chiari’s network. The handling of complex catheters in the RA has a potential risk of entrapment with Chiari’s network.

Introduction Tramadol, a weak opioid anesthetic, is used for pain management in patients with cancer, but the effects of tramadol on cancer via p-opioid receptor are still unknown. We assessed the effects of tramadol on pancreatic ductal adenocarcinoma using transgenic mice (LSL-KrasG12D/+; 7rp53flox/flox; Pdx-7cre/+). Methods Six-week-old transgenic mice were orally administered 10 mg/kg/day tramadol (n=12), 10 mg/kg/day tramadol and 1 mg/kg/day naltrexone (n=9), or vehicle water (n=14) until the humane endpoint. Cancer- related pain and plasma cytokine levels were assessed by the mouse grimace scale and cytokine array, respectively. Tumor status was determined histopathologically. Tramadol's effects on proliferation and invasion in pancreatic ductal adenocarcinoma cell lines were studied in vitro. Results Tramadol with/without naltrexone improved mouse grimace scale scores while decreasing inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. Proliferative Ki-67 and cyclins decreased by tramadol, while local M1-like tumor-associated macrophages increased by tramadol, which was blocked by naltrexone. Meanwhile, tramadol with/without naltrexone reduced juxta-tumoral cancer-associated fibroblasts and M2-like tumor-associated macrophages. Tumor-associated neutrophils, natural killers, and cytotoxic T cells were not altered. Tramadol decreased the proliferative and invasive potentials of pancreatic ductal adenocarcinoma cell lines via decreasing cyclins/cyclin-dependent kinases, which was partially reversed by naltrexone. Conclusions These findings imply that tramadol might be a useful anesthetic for pancreatic ductal adenocarcinoma: inhibiting the proliferation and invasion along with increasing antitumor M1-like tumor-associated macrophages via the p-opioid receptor, while improving cancer-associated pain possibly through the antitumor effects with the decrease of inflammatory cytokines. [ABSTRACT FROM AUTHOR]