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Cochlear implants (CIs) are generally considered useful in the treatment of hereditary hearing loss with progressive deafness. Early CI can be beneficial for maintaining social activities in POU4F3 mutation patients.

Objectives This study sought to isolate arrhythmogenic Marshall bundles (MBs) by radiofrequency (RF) catheter ablation. Background The vein of Marshall (VOM) is surrounded by a muscular bundle called the MB. The MB is 1 of the arrhythmogenic sources of atrial fibrillation (AF) and electrically connects to either the left atrial (LA) myocardium or coronary sinus (CS) musculature. By eliminating such electric connections using RF catheter ablation, the MB might be electrically isolated. Methods This retrospective study included 20 patients (64 ± 10 years old, 5 women) who underwent an MB isolation for nonparoxysmal AF. After pulmonary vein isolation, we performed venography of the VOM and inserted a 2-F electrode catheter into the VOM. RF applications were delivered to eliminate the MB electrograms from both the LA and CS when the MB was considered arrhythmogenic. Results MB isolation was achieved in 14 patients (70%). Of them, complete or partial MB isolation was accomplished in 7 patients (35%) each. The average number of RF applications in the LA (35 W, 30 s) and CS (25 W, 30 s) was 15 ± 14 and 4 ± 3, respectively. No severe adverse events were observed. During a follow-up of 23 ± 11 months, 18 patients (90%) maintained sinus rhythm. Conclusions RF applications targeting recordings from an electrode catheter in the VOM were feasible, and the MB could be electrically isolated. Elimination of the MB potentials would be a clear endpoint for patients with an arrhythmogenic MB.

Firefly bioluminescence is broadly applied as a noninvasive imaging modality in the biomedical research field. One limitation in firefly bioluminescence imaging is the limited variety of luciferins emitting in the near-infrared (NIR) region (650-900 nm), where tissue penetration is high. Herein, we describe a series of structure-inherent NIR emitting firefly luciferin analogues, NIRLucs, designed through a ring fusion strategy. This strategy resulted in pH-independent structure-inherent NIR emission with a native firefly luciferase, which was theoretically supported by quantum chemical calculations of the oxidized form of each luciferin. When applied to cells, NIRLucs displayed dose-independent improved NIR emission even at low concentrations where the native d-luciferin substrate does not emit. Additionally, excellent blood retention and brighter photon flux (7-fold overall, 16-fold in the NIR spectral range) than in the case of d-luciferin have been observed with one of the NIRLucs in mice bearing subcutaneous tumors. We believe that these synthetic luciferins provide a solution to the longstanding limitation in the variety of NIR emitting luciferins and pave the way to the further development of NIR bioluminescence imaging platforms.

Background A lower cut-off of the oesophageal temperature (ET) during catheter ablation of atrial fibrillation (AF) should be safer, but its durability may become in question. We evaluated an ET cut-off of 38 °C with an output of 25 W on the posterior wall. Methods In 636 consecutive patients (age: 60 ± 10 years, male: 542, paroxysmal AF: 405, CHADS2 score: 0.7 ± 0.9), an ET probe was utilised in 303 patients (259 pulmonary vein isolations [PVIs] and 44 simultaneous isolations of the posterior wall and all PVs box isolations [BOXIs]). When the ET increased to >38 °C, the radiofrequency delivery was switched off and the ablation point was tagged as an “EsoTag” by the CARTO™ system (Biosense Webster, Irvine, CA, USA). We analysed the characteristics of the ablation lesions at the EsoTags with respect to the dormant conduction, gaps in the redo-session, and ablation outcome. Results EsoTags were identified in 94.6% of the left PVIs and all BOXIs, and dormant conduction at the EsoTags was identified in 12.0% and 6.8%, respectively. In 10,796 ablation points, the ablation at the EsoTags that were associated with dormant conduction had a significantly shorter duration, smaller force-time integral, and smaller Δimpedance. The duration of an ET of >38 °C was significantly and positively correlated with the body mass index and negatively with the left atrial appendage flow velocity. During the redo-sessions in a 10.5 ± 6.0 months of follow-up (PVI: 14.7%, BOXI: 11.4%), reconnections at the EsoTags with dormant conduction were observed only in two patients after the PVI. The AF survival rate did not significantly differ in the presence of dormant conduction at the EsoTags (83.1% vs. 75.0%, p = 0.696). There were no patients hospitalised for gastroparesis. Conclusions Atrial fibrillation ablation utilising an oesophageal temperature cut-off of 38 °C might be safe and durable.

Introduction An electrical superior vena cava (SVC) isolation from the right atrium (RA) sometimes can be challenging. For a safe and efficient SVC isolation, we aimed to visualize the accurate position of the SVC-RA junction on a three-dimensional (3D) mapping system using the decremental conduction properties of the SVC-RA junction in patients with atrial fibrillation (AF). Methods This study consisted of 15 consecutive AF patients (11 males, age 59 ± 10 years). A 3D mapping catheter was positioned in the SVC-RA junction region while delivering a single extra-stimulus from the right atrial appendage (RAA), to discriminate the RA and SVC potentials. The electrophysiological SVC-RA junction was defined as the most proximal points where the SVC potentials were recorded, which were tagged on the 3D mapping system around the SVC-RA junction, where radiofrequency energy applications were applied. Results Around the SVC-RA junction, 9 ± 2 points were tagged on the 3D mapping system. The highest and lowest SVC-RA junction points were located on the anterior wall and posterior wall, respectively. The difference in the level between the highest and lowest SVC-RA junction points was 16.2 ± 6.3 mm. A successful SVC isolation was obtained in all patients without any complications. Conclusion The plane of the electrophysiologically defined SVC-RA junction was not perpendicular to the body axis, but slanted due to the anterior side being higher. Recognizing the precise location of the SVC-RA junction would contribute to a safe and efficacious SVC isolation.

Suppression of axillary lymph node metastasis (ALNM) is an important goal in the treatment of breast cancer. While several therapies directed to ALNM have been evaluated, effective and safe treatments for ALNM in triple negative breast cancer (TNBC) have not been established yet, especially against initial/small metastases. Here, we demonstrated the therapeutic effect of an anthracycline drug, epirubicin (EPI)-loaded polymeric micelles equipped with pH-triggered drug release property (EPI/m) against ALNM of TNBC. EPI/m effectively inhibited the spread of the primary tumor and the growth of ALNM, through selective accumulation and penetration in both primary tumor and vascularized ALNM, as well as efficient drug activation triggered by the intratumoral acidic environment. Furthermore, we revealed that the improvement of the activated drug distribution of EPI/m contributed to dose-dependent enhancement of the antitumor effect through expansion of the therapeutic window. These findings highlight the utility of pH-responsive property in EPI/m for the treatment of ALNM in TNBC.

Objectives This randomized study compared uninterrupted rivaroxaban therapy with warfarin therapy as prophylaxis against catheter ablation (CA)-induced asymptomatic cerebral infarction (ACI) and identified the risk factors of rivaroxaban. Background The reported incidence of ACI during CA for atrial fibrillation (AF) remains at 10% to 30%, and periprocedural oral anticoagulation could affect this incidence. Methods Patients with nonvalvular AF undergoing radiofrequency CA were randomly assigned to receive either uninterrupted rivaroxaban or warfarin as periprocedural anticoagulation therapy. CA was performed after at least 1 month of adequate anticoagulation. Cerebral magnetic resonance imaging (MRI) was performed within 2 weeks before and 1 day after CA to detect ACI. Results A total 132 patients were enrolled; 127 (median: 60.0 years of age; 83.5% males; 64.6% incidence of paroxysmal AF) complied with the study protocol and were analyzed; 64 patients received rivaroxaban, and 63 patients received warfarin. The rates of CA-induced ACI in the rivaroxaban group (15.6% [10 of 64 patients]) were similar to those in the warfarin group (15.9% [10 of 63 patients]; p = 1.000). No thromboembolic events developed; no differences in major or nonmajor bleeding rates were observed between the 2 drug groups (3.1% vs. 1.6%, respectively, or 18.8% vs. 19.0%, respectively). Multiple regression analysis indicated that the presence of deep and subcortical white matter hyperintensity (p = 0.002; odds ratio [OR]: 5.323) and the frequency of cardioversions (p = 0.016; OR: 1.250) were associated with the incidence of ACI. Conclusions No notable differences were found between the incidence of CA-induced ACI in the rivaroxaban group and that in the warfarin group in this randomized study.

Sonodynamic therapy (SDT) is currently considered as one of the promising minimally invasive treatment options for solid cancers. SDT is based on the combined use of a sonosensitizer drug and high-intensity focused ultrasound (HIFU) to produce cytotoxic reactive oxygen species (ROS) in and around neoplastic cells. Anthracycline drugs, including epirubicin (EPI), have been well known as effective sonosensitizers after interaction with focused ultrasound. Recently a new anticancer drug delivery system (DDS), NC-6300, has been developed that comprises EPI through an acid–labile hydrazone bond. In previous in vivo studies, NC-6300 showed basic drug safety and an excellent concentration property of EPI, and recently has been tested in clinical trials. For realizing minimally invasive cancer treatment, the present study demonstrated the effectiveness and feasibility of DDS-based SDT, which combined a small dose of NC-6300 and low energy of HIFU in mouse models of colon cancer and pancreatic cancer.

Recalcitrant head and neck squamous cell carcinoma (HNSCC) usually relapses after therapy due to the enrichment of drug resistant cancer stem-like cells (CSCs). Nanomedicines have shown potential for eradicating both cancer cells and CSCs by effective intratumoral navigation for reaching particular cell populations and controlling drug delivery. The installation of ligands on nanomedicines is an attractive approach for improving the delivery to CSCs within tumors, though the development of CSC-selective ligand-receptor systems has been challenging. Herein, we found that the CSC subpopulation in HNSCC cells overexpresses αvβ5 integrins, which is preferentially expressed in tumor neovasculature and cancer cells, and can be effectively targeted by using cyclic Arg-Gly-Asp (cRGD) peptide. Thus, in this study, we propose installing cRGD peptide on micellar nanomedicines incorporating cisplatin for improving their activity against CSCs and enhancing survival. Both cisplatin-loaded micelles (CDDP/m) and cRGD-installed CDDP/m (cRGD-CDDP/m) were effective against HNSCC SAS-L1-Luc cells in vitro, though cRGD-installed CDDP/m was more potent than CDDP/m against the CSC fraction. In vivo, the cRGD-CDDP/m also showed significant antitumor activity against HNSCC orthotopic tumors, i.e. SAS-L1 and HSC-2. Moreover, cRGD-CDDP/m rapidly accumulated into the lymph node metastasis of SAS-L1 tumors, effectively inhibiting their growth, and prolonging mice survival. These findings indicate cRGD-installed nanomedicines as an advantageous strategy for targeting CSCs in HNSCC, and particularly, cRGD-CDDP/m as a significant therapeutic strategy against regionally advanced HNSCC.

// Hiroaki Taniguchi 1 , Daisuke Hoshino 2 , Chiharu Moriya 1 , Hitoshi Zembutsu 3 , Nobuhiro Nishiyama 4 , Hiroyuki Yamamoto 5 , Kazunori Kataoka 6 and Kohzoh Imai 1, 7 1 The Center for Antibody and Vaccine Therapy, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan 2 Cancer Biology Department, The Kanagawa Cancer Center Research Institute, Kanagawa 241-0815, Japan 3 Division of Genetics, National Cancer Center Research Institute, Tokyo 104-0045, Japan 4 Polymer Chemistry Division, Chemical Resources Laboratory, Tokyo Institute of Technology, Kanagawa 226-8503, Japan 5 Department of Gastroenterology and Hepatology, School of Medicine, St. Marianna Medical University, Kanagawa 216-0015, Japan 6 Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan 7 The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan Correspondence to: Hiroaki Taniguchi, email: h-tani@ims.u-tokyo.ac.jp Keywords: breast cancer stem cell, cancer stemness, epigenetic alterations, nucleic acid medicine, PRDM14 Received: November 11, 2016 Accepted: March 22, 2017 Published: April 01, 2017 ABSTRACT PR domain zinc finger protein 14 (PRDM14) maintains stemness in embryonic stem cells via epigenetic mechanisms. Although PRDM14 is elevated in several cancers, it is unclear if and how PRDM14 confers stem cell-like properties and epigenetic changes to cancer cells. Here, we examined the phenotypic characteristics and epigenetic and gene expression profiles of cancer cells that differentially express PRDM14, and assessed the potential of PRDM14-targeted cancer therapy. PRDM14 expression was markedly increased in many different cancer types and correlated with poor survival of breast cancer patients. PRDM14 conferred stem cell-like phenotypes to cancer cells and regulated the expression of genes involved in cancer stemness, metastasis, and chemoresistance. PRDM14 also reduced the methylation of proto-oncogene and stemness gene promoters and PRDM14-binding regions were primarily occupied by histone H3 Lys-4 trimethylation (H3K4me3), both of which are positively correlated with gene expression. Moreover, strong PRDM14 binding sites coincided with promoters containing both H3K4me3 and H3K27me3 histone marks. Using calcium phosphate hybrid micelles as an RNAi delivery system, silencing of PRDM14 expression by chimera RNAi reduced tumor size and metastasis in vivo without causing adverse effects. Conditional loss of PRDM14 function also improved survival of MMTV-Wnt-1 transgenic mice, a spontaneous model of murine breast cancer. Our findings suggest that PRDM14 inhibition may be an effective and novel therapy for cancer stem cells.

// Takahiko Nishiyama 1 , Takehiro Kimura 1 , Taishi Fujisawa 1 , Kazuaki Nakajima 1 , Akira Kunitomi 1 , Shin Kashimura 1 , Yoshinori Katsumata 1 , Nobuhiro Nishiyama 1 , Yoshiyasu Aizawa 1 , Keiichi Fukuda 1 and Seiji Takatsuki 1 1 Department of Cardiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, 160-8582, Japan Correspondence to: Takahiko Nishiyama, email: ntakahiko914@keio.jp Keywords: catheter ablation, perimitral atrial flutter, mitral isthmus, artial fibrillation, steerable sheath Received: February 04, 2017 Accepted: March 11, 2017 Published: April 13, 2017 ABSTRACT Background: For perimitral atrial flutter (PMFL) developing after catheter ablation of atrial fibrillation (AF), to create a complete conduction block at the mitral isthmus (MI) is mandatory to terminate it, however, it is still challenging. Methods: This study consisted of 80 patients (74 male, 61 ± 8.1 years) undergoing MI ablation. After a circular mapping catheter was positioned at the neck of the left atrial appendage (LAA), the MI ablation was performed on the MI line just below the LAA neck targeting the earliest activation recording site of the LAA catheter during pacing from the coronary sinus (CS). When ablation during CS pacing was not successful, an RF delivery during LAA pacing was applied targeting the earliest activation site just below the MI line. If the endocardial approach failed, an RF application inside the CS was attempted. Results: With the endocardial approach, acute success was achieved in 51/80 patients (64%). Additional epicardial ablation from the CS was performed in 26/29 (90%) endocardially unsuccessful patients and conduction block at the MI was achieved in 21/26 (81%). Overall, complete conduction block at the MI was achieved in 72/80 patients (90%). At a mean follow-up of 16 ± 6 months, 20 patients (25%) had recurrence of atrial arrhythmias (AT: 12, AF: 8), and 10 (AT: 7, AF : 3) underwent a second procedure in which an LMI block line was completed in 3 (33%). PMFL was diagnosed in 6 out of 7 AT patients. No complications were observed. Conclusions: Creating linear lesions just beneath the neck of the LAA was highly successful under the guidance of a circular mapping catheter in the LAA using a steerable sheath. An RF application from the CS was needed in less than half of the cases.

The subcutaneous implantable cardioverter-defibrillator (S-ICD) is a useful option for patients with a single ventricle (SV) in which transvenous leads are contraindicated because of intracardiac shunts. We report a case in which a right parasternal lead placement was indicated for an S-ICD in a resuscitated patient with an SV. There were significant changes in the magnitude of R to T waves ratio in the right compared to the left parasternal lead position. Screening in the right parasternal position is effective for selecting appropriate patients with congenital heart disease for S-ICD implantations.

Sonodynamic therapy (SDT) is a minimally invasive anticancer therapy involving a chemical sonosensitizer and high-intensity focused ultrasound (HIFU). SDT enables the reduction of drug dose and HIFU irradiation power compared to those of conventional monotherapies. In our previous study, mouse models of colon and pancreatic cancer were used to confirm the effectiveness of SDT vs. drug-only or HIFU-only therapy. To validate its usefulness, we performed a clinical trial of SDT using an anticancer micelle (NC-6300) and our HIFU system in four pet dogs with spontaneous tumors, including chondrosarcoma, osteosarcoma, hepatocellular cancer, and prostate cancer. The fact that no adverse events were observed, suggests the usefulness of SDT.

Background We aimed to clarify the cost-effectiveness of an expensive combination therapy for atrial fibrillation (AF) using both catheter ablation and dabigatran compared with warfarin at each CHADS2 score for patients in Japan. Methods A Markov model was constructed to analyze costs and quality-adjusted life years associated with AF therapeutic options with a time horizon of 10 years. The target population was 60-year-old patients with paroxysmal AF. The indication for anticoagulation was determined according to the Japanese guideline. Anticoagulation-related data were derived from the RE-LY study and the AF recurrence rate was set at 2.7% per month during the first 12 months and at 0.40% per month afterwards. Stroke risk was determined according to AF recurrence, anticoagulation, and CHADS2 score. The risks for stroke recurrence and stroke death were also considered. Costs were calculated from the healthcare payer's perspective, and only direct medical costs were included. Results Warfarin was the most preferred option for patients with a CHADS2 score of 0 from a health economics aspect. Ablation under warfarin was preferred for a CHADS2 score of 1–3, while ablation under dabigatran was preferred for a CHADS2 score ≥4. The quality of life score for AF had the largest impact on the incremental cost-effectiveness ratios in the analysis between the anticoagulation arm and the anticoagulation + ablation arm for a CHADS2 score of 2. Within the range of the Japanese willingness-to-pay threshold (¥5,000,000), the ablation + warfarin arm became the best option with its probability of 81.7% for a CHADS2 score of 2; the dabigatran + ablation arm was the most preferred option with its probability of 56.1% for a CHADS2 score of 4. Conclusions Ablation under dabigatran therapy is an expensive therapeutic option, but it might benefit patients with a low quality of life and a high CHADS2 score.

Differences in the methodologies for evaluating atrial fibrillation (AF) ablation outcomes should be evaluated. In the present study, we compared the AF ablation outcomes among periodic clinic electrocardiography (ECG), 24-h Holter ECG, and telemonitoring ECG to evaluate the differences among these methods. In addition, we evaluated the AF-free survival rate for each method with different durations of the blanking period. A total of 30 AF patients were followed up for 6 months after initial catheter ablation, with clinic ECG on every clinic visit, monthly 24-h Holter ECG, and telemonitoring ECG twice daily and upon symptoms. AF relapse was defined as AF or atrial tachycardia detected with any of the methods. Two patients dropped out of the study, and 28 patients were followed up for 8.8 ± 2.7 months. Patients underwent 3.6 ± 0.8 clinic ECG, 5.1 ± 0.8 Holter ECG, and 273 ± 68 telemonitoring ECG examinations. During the first, second, third, fourth, fifth, and sixth months of follow-up, Holter ECG detected relapses in 11.1, 8.3, 11.5, 15.4, 4.2, and 4.8 % of patients and telemonitoring ECG detected relapses in 32.1, 25.0, 25.0, 17.9, 28.6, and 17.9 % of patients, respectively. When no duration was set for the blanking period, the AF-free survival rate was significantly lower with telemonitoring ECG (46.4 %) than with Holter ECG (78.6 %, P = 0.013) or clinic ECG (85.7 %, P = 0.002). In addition, when the duration of the blanking period was set to 3 months, the AF-free survival rate was significantly lower with telemonitoring ECG than with clinic ECG (92.9 vs. 71.4 %, P = 0.041). The AF ablation outcomes with twice-daily telemonitoring ECG might differ from those with clinic ECG when the duration of the blanking period is 0-3 months. A follow-up based solely on clinic ECG might underestimate AF recurrence.

In patients with Brugada syndrome (BS), VF occurred predominantly during the nocturnal period. Some patients also developed ESs. In addition to the circadian rhythm, patients showed weekly and seasonal patterns. The patients with ESs had peak episodes of VF on Saturday and in the winter and spring, while episodes of VF in patients with single VF events occurred most often on Monday with smaller seasonal variation. Except for age, there was no difference in the clinical or ECG characteristics between the patients with ESs and those with single VF episodes.

Eventual relapse of tumor growth is commonly observed in head and neck cancer patients, following treatment with platinum-based chemotherapies. This occurrence is believed to be related to the failure to eradicate drug resistant, cancer stem cell (CSC) niches, thereby enriching their population in tumors after treatment. In this study, we show that in contrast to free cisplatin (CDDP), the polymer micelle-based nanomedicine incorporating cisplatin (CDDP/m), can eradicate both the undifferentiated cell and the differentiated cancer cell populations within a head and neck tumor model. Immunohistochemistry of treated tumors showed that opposing to CDDP treatment, CDDP/m could reduce tumor growth without concentrating the CSC-like population. We further showed that CDDP/m, but not CDDP, can localize into hypoxic regions, possibly CSC-rich areas, in the tumors, and can overcome their detoxification mechanism based-on high cellular expression of glutathione to successfully deliver Pt to nuclear DNA. Our data suggests CDDP/m to be a replacement for current platinum therapies, for its ability to eradicate both bulk and CSC-like populations, and in turn to prevent recurrence of tumor growth.

A 50-year-old man with a history of undergoing catheter ablation twice, 10 and 7 years ago, for persistent atrial fibrillation (AF) underwent the third catheter ablation for paroxysmal AF that recurred 3 years ago. He had no history of cardiac surgery. Coronary sinus (CS) ostial atresia was pointed

A more immediate impact for therapeutic approaches of current clinical research efforts is of major interest, which might be obtained by developing a noninvasive radiation dose-escalation strategy, and neutron capture therapy represents one such novel approach. Furthermore, some recent researches on neutron capture therapy have focused on using gadolinium as an alternative or complementary for currently used boron, taking into account several advantages that gadolinium offers. Therefore, in this study, we carried out feasibility evaluation for both single and multiple injections of gadolinium-based MRI contrast agent incorporated in calcium phosphate nanoparticles as neutron capture therapy agent.In vivo evaluation was performed on colon carcinoma Col-26 tumor-bearing mice irradiated at nuclear reactor facility of Kyoto University Research Reactor Institute with average neutron fluence of 1.8 × 10(12) n/cm(2). Antitumor effectivity was evaluated based on tumor growth suppression assessed until 27 days after neutron irradiation, followed by histopathological analysis on tumor slice.The experimental results showed that the tumor growth of irradiated mice injected beforehand with Gd-DTPA-incorporating calcium phosphate-based nanoparticles was suppressed up to four times higher compared to the non-treated group, supported by the results of histopathological analysis.The results of antitumor effectivity observed on tumor-bearing mice after neutron irradiation indicated possible effectivity of gadolinium-based neutron capture therapy treatment.

Background The mechanism underlying the associations of sleep-disordered breathing (SDB) with stroke and atrial fibrillation (AF) is not well established. We explored the relationship between nocturnal intermittent hypoxia, a marker of SDB, and left atrial (LA)/LA appendage (LAA) function among AF patients. Methods We evaluated 134 consecutive AF candidates for catheter ablation (age, 59.6 ± 9.4 years; body mass index [BMI], 24.8 ± 3.2; C ongestive Heart Failure, H ypertension, A ge (≥75 years), D iabetes, S troke/Transient Ischemic Attack, V ascular Disease, A ge (65-74 years), S ex (Female) (CHA 2 DS 2 -VASc) score, 1.2 ± 1.1, paroxysmal AF, n = 83) using nocturnal pulse oximetry, a noninvasive screening method for nocturnal intermittent hypoxia. Based on 3% oxygen desaturation index (3% ODI), patients were divided into nocturnal intermittent hypoxia (3% ODI > 15; n = 32) and control groups (3% ODI ≤ 15; n = 102). Results The nocturnal intermittent hypoxia group demonstrated significantly higher weight, BMI, C ongestive Heart Failure, H ypertension, A ge, D iabetes, S troke/Transient Ischemic Attack (CHADS 2 ) and CHA 2 DS 2 -VASc scores, serum hemoglobin A1c and plasma brain natriuretic peptide levels, LA size, and prevalence of hypertension, vascular disease, and sick sinus syndrome. Echocardiographically, nocturnal intermittent hypoxia was associated with a higher grade of spontaneous echo contrast and low LAA flow velocity. Multiple regression analysis adjusted for type of AF, CHA 2 DS 2 -VASc score, BMI, plasma brain natriuretic peptide level, LA size, and rhythm on echocardiography revealed that 3% ODI was a factor independently associated with LAA flow velocity (β = −0.184; 95% confidence interval, −0.818 to −0.006). Conclusions Nocturnal intermittent hypoxia was an independent determinant for low LAA flow velocity in patients with AF, suggesting that the connection between SDB and LAA function might underlie the association of AF with stroke.

Aims The left atrial appendage (LAA) represents the major source of cardiac thrombus formation in patients with atrial fibrillation (AF). Phased-array intracardiac echocardiography (ICE) has become available and frequently used during catheter ablation of AF. We attempted to study the feasibility of using ICE for the visualization and evaluation of the LAA from the pulmonary artery (PA) in patients with AF. Methods and Results Eighty patients with AF undergoing catheter ablation (70 males, 57.5 ± 9.1 years) were included. Transoesophageal echocardiography was performed on the prior day before the catheter ablation, and ICE was performed just before the transseptal puncture during the catheter ablation. The ICE catheter was advanced up into the PA from the femoral vein, where the LAA was clearly and entirely visualized by manipulating the ICE catheter. We compared the degree of spontaneous echo contrast, and the correlation was obtained between the ICE and TEE ( κ = 0.534, P < 0.001). Furthermore, the LAA flow velocity (LAA emptying and filling velocities) measured by ICE had a good correlation to that measured by TEE ( R = 0.872, P < 0.01 and R = 0.753, P < 0.01, respectively). No patients developed any complications. Conclusion The utilization of ICE in the PA is feasible for the observation and evaluation of the LAA.

Background It has never been possible to immediately evaluate heart rate variability ( HRV ) during exercise. We aimed to visualize the real‐time changes in the power spectrum of HRV during exercise and to investigate its relationship to the ventilatory threshold ( VT ). Methods and Results Thirty healthy subjects (29.1±5.7 years of age) and 35 consecutive patients (59.0±13.2 years of age) with myocardial infarctions underwent cardiopulmonary exercise tests with an RAMP protocol ergometer. The HRV was continuously assessed with power spectral analyses using the maximum entropy method and projected on a screen without delay. During exercise, a significant decrease in the high frequency ( HF ) was followed by a drastic shift in the power spectrum of the HRV with a periodic augmentation in the low frequency/ HF (L/H) and steady low HF . When the HRV threshold ( HRVT ) was defined as conversion from a predominant high frequency ( HF ) to a predominant low frequency/ HF (L/H), the VO 2 at the HRVT ( HRVT ‐ VO 2 ) was substantially correlated with the VO 2 at the lactate threshold and VT ) in the healthy subjects ( r =0.853 and 0.921, respectively). The mean difference between each threshold (0.65 mL/kg per minute for lactate threshold and HRVT , 0.53 mL/kg per minute for VT and HRVT ) was nonsignificant ( P >0.05). Furthermore, the HRVT ‐ VO 2 was also correlated with the VT ‐ VO 2 in these myocardial infarction patients ( r =0.867), and the mean difference was −0.72 mL/kg per minute and was nonsignificant ( P >0.05). Conclusions A HRV analysis with our method enabled real‐time visualization of the changes in the power spectrum during exercise. This can provide additional information for detecting the VT .

Aims Photodynamic therapy (PDT) is based on non-thermal injury mediated by singlet oxygen species and is used clinically in cancer therapy. In our continuing efforts to apply this technology to cardiac catheter ablation, we clarified the optimal condition for creating PDT-mediated lesions using a laser catheter. Methods and results In a total of 35 canines, we applied a laser directly to the epicardium of the beating heart during open-chest surgery at 15 min after administration of a photosensitizer, talaporfin sodium. We evaluated the lesion size (depth and width) using hematoxylin-eosin staining under varying conditions as follows: laser output (5, 10, 20 W/cm2), irradiation time (0–60 s), photosensitizer concentration (0, 2.5, 5 mg/kg), blood oxygen concentration (103.5 ± 2.1 vs. 548.0 ± 18.4 torr), and contact force applied during irradiations (low: 20 g). A laser irradiation at 20 W/cm2 for 60 s under 5 mg/kg (29 µg/mL) of photosensitizer induced a lesion 8.7 ± 0.8 mm deep and 5.2 ± 0.2 mm wide. The lesion size was thus positively correlated to the laser power, irradiation time, and photosensitizer concentration, and was independent of the applied contact force and oxygen concentration. In addition, the concentration of the photosensitizer strongly correlated with the changes in the pulse oximetry data and fluorescence of the backscattering laser, suggesting that a clinically appropriate condition could be estimated in real time. Conclusion Photodynamic therapy-mediated cardiac lesions might be controllable by regulating the photosensitizer concentration, laser output, and irradiation time.

At 19 years of age, a woman experiencing dyspnea on exertion was diagnosed with idiopathic pulmonary arterial hypertension. Pulmonary arterial hypertension–targeted drugs (oral beraprost, sildenafil, tadalafil, macitentan, and subcutaneous treprostinil) were administered sequentially. However, the patient’s symptoms, World Health Organization functional class II or III, persisted. The patient refused to start intravenous epoprostenol because of cosmetic concerns and was referred to our hospital at 38 years of age. Right-sided heart catheterization revealed mean pulmonary arterial pressure of 72 mm Hg and pulmonary vascular resistance of 13.0 Wood units. The patient developed right-sided heart failure twice within 1 year, which was poorly controlled by conventional therapy. Previous studies have reported that pulmonary artery denervation with radiofrequency catheter ablation of the pulmonary artery trunk significantly improves pulmonary hypertension.1,2 We undertook a clinical study to investigate a novel method of pulmonary artery denervation using a commercially available radiofrequency ablation catheter, in part because the circular ablation …

Background: The monitoring of the effects of direct oral anticoagulants may be beneficial during emergencies and adverse events. We aimed to explore direct oral anticoagulant monitoring in “real-world” settings, in which monitoring methods are limited and loading time can be estimated based on only patient reports. Methods: In 164 patients, plasma anti-Xa activity was assessed using a STA ® -Liquid Anti-Xa reagent (Diagnostica Stago, Asnieres, France), and prothrombin time was measured using HemosIL ® RecombiPlasTin 2G (Instrumentation Laboratory, Bedford, MA, USA). The loading time was calculated according to the previous dosing time reported by the patient. In the clinic setting, rivaroxaban and apixaban were administered to 103 patients with atrial fibrillation and a blood sample was tested once during a clinic visit. In the hospitalization setting, edoxaban was administered to 61 patients undergoing arthroplasty for prophylaxis of a venous thrombosis and blood samples were tested 3 and 18 h after the last intake. Results: Plasma Xa activity in the clinical setting ranged widely (rivaroxaban: 1.1–424.4 ng/mL, apixaban: 15.4–469.2 ng/mL) during the 11.7 ± 7.0 h following the previous dose. The values varied over a wide range (up to a factor of 2) at the same loading time, especially around the peak period. The plasma anti-Xa activity of rivaroxaban and apixaban showed linear correlations with prothrombin time (R 2 = 0.828 and 0.717, respectively). Edoxaban administration prolonged the prothrombin time by only 1.6 ± 1.1 s from the trough to the peak, to a degree that was negatively correlated with age, but not with plasma creatinine level, creatinine clearance, or body mass index. Conclusion: In real-world settings, plasma anti-Xa monitoring should be interpreted considering the wide variations in data, reflecting the variability in patient-reported loading time and interpatient variability.

Performance measures (PMs) are used to accelerate translation of scientific evidence into clinical practice. However, it remains unknown how they are applied in the real world and whether the compliance to these metrics will lead to improved patient's outcome in atrial fibrillation (AF). Within the Japanese multicenter AF registry (n = 1,874), adherence of the AF PMs (based on 2016 American Heart Association/American College of Cardiology criteria) and its association with quality of life scaling and clinical outcomes was evaluated. The patient was deemed “adherent” when all applicable components of the PMs for outpatient settings (CHA 2 DS 2 -VASc risk score documentation [PM-4], anticoagulation prescribed [PM-5], and monthly international normalized ratio (INR) for warfarin treatment [PM-6]) were satisfied. The Atrial Fibrillation Effect on Quality of Life (AFEQT) questionnaire was assessed at baseline and 1 year. About a half of patients (46.1%) were adherent to the AF PMs. PMs were more frequently achieved in patients managed with rhythm control compared with rate control. The achievement rate for each component was 53.9% for PM-4, 85.6% for PM-5, and 90.3% for PM-6, respectively. Although AFEQT global scores at baseline were similar (median 79.2 [interquartile ranges 66.7 to 88.5] vs 77.1 [64.8 to 88.0], p = 0.227), AFEQT global scores at 1-year follow-up were significantly greater in adherence group than those in nonadherence group (89.2 [78.5 to 96.6] vs 86.7 [76.7 to 95.0], p = 0.021). This tendency was consistent regardless of therapeutic strategies. There remains an important opportunity to improve the quality of care in patients with AF. Adherence to the AF PMs might lead to the improvement of patient's quality of life.

We performed contact force (CF) monitoring during pulmonary vein (PV) isolation to evaluate CF according to sheath type, catheter position, and inadequate ablation.Thirty consecutive patients (paroxysmal atrial fibrillation, 23; CHADS2 score, 0.5 ± 0.7; age, 56 ± 10 years) who underwent PV isolation using a CF-sensing catheter were included. Data for operator-blinded CF, impedance, and duration of the "first touch" (first round of ablation in each PV) was collected. We compared the CF, maximum CF, force-time integral, average impedance, and impedance drop (Δ impedance) between different sheaths (Swartz™ vs. Agilis™) in 12 different catheter positions, and in inadequate first touches requiring additional ablation.A total of 1283 ablation points (Swartz™, 620 points; Agilis™, 663 points) were evaluated. The average CF was significantly higher in the Agilis™ group (17.8 ± 13.0 g) than the Swartz™ group (15.0 ± 12.4 g; P0.001), especially in the anterior, inferior-anterior, and inferior-posterior sections of the right PV, and the top of the roof, and calina of the left PV. The Δ impedance showed a mildly significant negative relationship with the average CF (r=-0.206; P0.001) and with the force-time integral (r = -0.279; P0.001). Compared to first touches, the average CF and Δ impedance were significantly smaller in inadequate first touches in the Swartz™ group, but not in the Agilis™ group.CF for PV isolation was significantly different depending on the position of the catheter and the type of sheath.

Background We investigated various serum inflammatory markers to predict ablation responders who have no atrial fibrillation (AF) relapse after the initial ablation. Methods Forty-four consecutive AF patients (age: 59 ± 8 years, paroxysmal: 31, CHADS 2 : 1.1 ± 1.1) who underwent an initial pulmonary vein isolation were investigated. Various serum inflammatory markers, such as adiponectin, ANP, BNP, 1CTP, F1+2, hs-CRP, IL-6, intact P1NP, MDA-LDL, MMP-2, TGF-β, TIMP-2, and TNF-α, were evaluated prior to ablation. AF relapse was defined as AF documented in telemonitoring electrocardiograms twice a day during 9.7 ± 2.4 months of follow-up with three months of a blanking-period. Results A total of 29 patients (paroxysmal: 21) maintained sinus rhythm after the initial catheter ablation. These ablation responders had significantly lower MMP-2 (Sinus vs. Relapsed: 748 ± 132.7 vs. 841.2 ± 152.4 ng/mL, P=0.042) and TNF-α (1.1 ± 0.4 vs. 1.8 ± 1.7 pg/mL, P=0.046) levels prior to ablation. A BNP-adjusted Cox multivariate regression analysis revealed that the independent predictive factor for AF recurrence was high MMP-2 levels (>766 ng/mL) accompanied by high TNF-α levels (>1.2 pg/mL). Conclusions The levels of MMP-2 and TNF-α might be useful for predicting initial AF catheter ablation responders.

Intermittent positional down beat nystagmus (p-DBN) is rare. We describe an unusual case of intermittent p-DBN which was induced by rotation, anteflexion, and lateral flexion of the neck. A 59-year-old man complained of loss of consciousness and lightheadedness. Positional testing revealed the p-DBN. The evoked p-DBN had latency and the patient had a feeling of passing out while the p-DBN was present. There were no abnormal findings in the vestibular functional examinations. Findings of the MRI were negative. MRA revealed no stenosis of the vertebral artery bilaterally, but there was an anatomical difference. The p-DBN characteristics were documented by electronystagmography during the positional test. The p-DBN lasted intermittently while maintaining the provoking position. It was found that p-DBN occurred with not only the rotation of the neck, but also in the anteflexion and lateral flexion of the neck. There was no stenosis of the vertebral artery (VA) on angiography, but we speculated that the cause of the p-DBN was the VA occlusion due to rotation, anteflexion, and lateral flexion of the neck.

The satisfaction level is one of the important parameters to evaluate the effectiveness of cochlear implant (CI) in adult CI users. The purpose of this study is to investigate what factor improves the satisfaction level in adult CI users. Questionnaires were used to evaluate the items concerning the satisfaction level. One hundred patients who underwent cochlear implant placement at or over the age of 20 years were enrolled in this study. All patients had an experience of at least 5 years of CI use. To evaluate the effect of CI, questionnaire items were answered about the common communicative methods, listening under various situations, points of dissatisfaction, useful level, anxiety level without CI, satisfaction level, and the duration of CI usage. Sixty two percent of the patients were satisfied with the effect of CI and 80% felt that their CI was useful. Their listening results tended to be better in quieter environments or conversation in small groups. Furthermore, listening was related to the useful and satisfaction levels. Therefore, the better they could hear, the more they were satisfied with their CI, and appreciated its usefulness. The frequency of using CI as a communicative method (application level of CI) was statistically related to useful level, but no statistical relationship was seen between the application level of CI and anxiety level or satisfaction levels. These results suggest that other factors such as psychological status might affect the satisfaction level in addition to the CI application level. We concluded that it was necessary for us to understand the listening level before CI surgery in order to predict the postoperative course and to give an appropriate explanation to the patients.

Electrophysiological Properties of the Superior Vena Cava and Venoatrial Junction Background Although the superior vena cava (SVC) has been well known to be one of the important foci triggering atrial fibrillation (AF), its electrophysiological characteristics have received little research attention. The aim of this study was to investigate the electrophysiological properties of the SVC and venoatrial junction (VAJ). Methods Twenty-five consecutive AF patients without structural heart disease undergoing electrical SVC isolation were included in this study. After pulmonary vein isolation, a circular decapolar catheter and 2 multipolar catheters were emplaced in the VAJ, right atrial appendage (RAA), and SVC, respectively. Burst pacing and single extrastimulus were applied from the RAA and SVC. The atrial and caval potentials on the circular catheter in the VAJ were investigated. Results Intracaval conduction delay and various degrees of conduction block over the VAJ were observed with burst pacing from both the RAA and SVC. A single extrastimulus from the RAA and SVC with a basic cycle length of 600 milliseconds prolonged the conduction time via the VAJ by 81 ± 49.7 milliseconds and 61 ± 58.7 milliseconds, respectively. The atrial and caval electrograms at the VAJ, which were separated from each other by pacing applications, facilitated mapping of the earliest activation site at the VAJ. Conclusions Intracaval conduction delay and decremental conduction property via the VAJ were demonstrated using pacing maneuvers. Pacing applications from the RAA or SVC can help distinguish the atrial and caval potentials and can facilitate mapping of the optimal ablation sites to isolate the SVC.

Background— The characteristic ECG of Brugada syndrome (BS) can be masked by complete right bundle-branch block (CRBBB) and exposed by resolution of the block or pharmacological or pacing maneuvers. Methods and Results— The study consisted of 11 patients who had BS and CRBBB. BS was diagnosed before the development of CRBBB, on the resolution of CRBBB, or from new characteristic ST-segment changes that could be attributable to BS. Structural heart diseases were excluded, and coronary spasm was excluded on the basis of a provocation test at catheterization. In 7 patients, BS was diagnosed before the development of CRBBB. BS was diagnosed when CRBBB resolved spontaneously (n=1) or by right ventricular pacing (n=3). The precipitating cause for the spontaneous resolution of CRBBB, however, was not apparent. On repeated ECGs, new additional upward-convex ST-segment elevation was found in V 2 or V 3 in 3 patients. In 2 patients, new ST-segment elevation was induced by class I C drugs. The QRS duration was more prolonged in patients with BS and CRBBB compared with age- and sex-matched controls: 170±13 versus 145±15 milliseconds in V 1 and 144±19 versus 128±7 milliseconds in V 5 (both P 1 was larger in the BS patients than in the control subjects ( P =0.0323), but that of R′ was similar ( P =0.0560). Conclusions— BS can coexist behind CRBBB, and CRBBB can completely mask BS. BS might be demonstrated by relief of CRBBB or by spontaneous or drug-induced ST-segment elevation. The prevalence, mechanism, and clinical significance of a combination of CRBBB and BS are yet to be determined.

Epstein syndrome is a rare disease which is accompanied by nephritis, sensorineural hearing impairment and macrothrombocytopenia. It has been suggested that this syndrome is a hereditary disease associated with mutations in MYH9, which encodes non-muscle myosin heavy chain IIA. We report a case of a patient with Epstein syndrome in whom bilateral profound hearing impairment developed and who had undergone cochlear implantation 9 years previously. Prior to this, the patient showed progressive sensorineural hearing impairment and had become completely deaf by the age of 25. A cochlear implant was successfully used with a speech discrimination score of 98% (sentence test). However, in the present case, peri- and postoperative complications occurred: tympanic perforation remained after a promontory stimulation test, followed by transitory otitis with purulent discharge. Therefore, tympanoplasty was performed simultaneously with cochlear implantation. These complications were considered to be caused by platelet dysfunction and delayed wound healing. Furthermore, cochlear destruction was observed 8 years postoperatively. In Epstein syndrome, the mechanism of osseous change remains uncertain. To the best of our knowledge, this is the first case report of Epstein syndrome in a patient with long-term use of a CI.

A substantial number of patients with idiopathic ventricular fibrillation (IVF) present with no specific electrocardiographic (ECG) findings.To evaluate complete right bundle branch block (RBBB) in patients with IVF.Patients with IVF showing complete RBBB were included in the present study. Structural and primary electrical diseases were excluded, and provocation tests were performed to exclude the presence of spastic angina or Brugada syndrome (BrS). The prevalence of complete RBBB and the clinical and ECG parameters were compared either in patients with IVF who did not show RBBB or in the general population and age and sex comparable controls with RBBB.Of 96 patients with IVF, 9 patients were excluded for the presence of BrS. Of 87 patients studied, 10 (11.5%) patients showed complete RBBB. None had structural heart diseases, BrS, or coronary spasms. The mean age was 44 ± 15 years, and 8 of 10 patients were men. Among the ECG parameters, only the QRS duration was different from that of the other patients with IVF who did not show complete RBBB. Ventricular fibrillation recurred in 3:2 in the form of storms, which were well suppressed by isoproterenol. Complete RBBB was found less often in control subjects (1.37%; P.0001), and the QRS duration was more prolonged in patients with IVF: 139 ± 10ms vs 150 ± 14ms (P = .0061).Complete RBBB exists more often in patients with IVF than in controls. A prolonged QRS complex suggests a conduction abnormality. Our findings warrant further investigation of the role of RBBB in the development of arrhythmias in patients with IVF.

Background Strokes develop even in patients with low CHADS 2 scores, and the left atrial appendage (LAA) is the embolic source 90% of the time. We focused on the LAA morphology as a new predictor of strokes. Objective To clarify the anatomical characteristics of the LAA for risk stratification of strokes in patients with nonvalvular atrial fibrillation (AF) who have low CHADS 2 scores. Methods Among 80 patients who underwent catheter ablation of AF with contrast-enhanced computed tomography, the LAA characteristics were compared between 30 patients with histories of strokes and 50 age-matched controls. The LAA anatomy was classified into 4 types—"cactus," "cauliflower," "chicken wing," and "windsock"—discriminated by the computed tomography measurements of the length, angle, and number of lobes of the LAA. Results The average CHADS 2 score did not differ significantly between patients with stroke and controls (0.8±0.8 vs 0.6±0.7; P = .277). Eight (26.7%) patients with stroke had CHA 2 DS 2 -VASc scores of 0. The left atrial size, LAA flow velocity, left ventricular function, and serum brain natriuretic peptide level were also unable to predict strokes. However, a "cauliflower" LAA, defined as a main lobe of less than 4 cm long without forked lobes, was significantly more common in patients with stroke (odds ratio 3.857; 95% confidence interval 1.482–10.037; P = .005). The CHA 2 DS 2 -VASc score-adjusted logistic regression analysis revealed the cauliflower LAA as an independent predictor of a stroke (odds ratio 3.355; 95% confidence interval 1.243–9.055; P = .017). Conclusions The LAA anatomy might be useful for predicting strokes in patients with nonvalvular AF who have low CHADS 2 scores.

Ridge-Related Reentry Introduction The ridge between the left pulmonary veins (PV) and the left atrial appendage composes part of the lateral mitral isthmus (LMI). Following circumferential PV isolation and LMI linear ablation for the treatment of atrial fibrillation (AF), a critical pathway might develop over the ridge leading to a ridge-related reentry (RRR). Methods and Results Out of 61 patients who underwent circumferential PV isolation appended by LMI ablation, 5 patients developed RRR. The diagnosis of RRR was based on (1) macro-reentrant atrial tachycardia involving the septum, anterior and inferior wall of the left atrium; (2) slow conduction along the ridge; (3) wide-split double potentials in the ventricular aspect of the LMI were identified with the coronary sinus (CS) electrodes. RRR was investigated with electroanatomical mapping and entrainment mapping and catheter ablation was carried out in all patients. The mean cycle length (CL) of RRR was 312 ± 82 milliseconds and the PPIs at the left atrial septum, inferior and anterior wall during RRR were 10 ± 6, 12 ± 8, 9 ± 5 milliseconds longer than the RRR CL. The interval of the double potentials recorded in the CS electrodes crossing the LMI was 164 ± 38 milliseconds during RRR and the PPI on the LMI near the mitral annulus was 57 ± 10 milliseconds longer than the RRR CL. Catheter ablation was performed anatomically by targeting the ridge and successfully terminated RRR. Conclusion After circumferential PV isolation and ablation for LMI in patients with AF, RRR can develop by utilizing the surviving myocardial tissue of the ridge as a critical pathway.

Patients with coronary spasm generally have a good prognosis, although it can result in sudden cardiac arrest (SCA) and syncope. We hypothesized that the nature of coronary spasm triggering lethal arrhythmias may be different from that which induces angina-only.Clinical characteristics were examined in patients who had experienced SCA (n = 18) or syncope (n = 28) triggered by coronary spasm. These characteristics were compared to those of patients who had coronary spastic angina-only (n = 52).SCA and syncope occurred frequently during daytime in 57% and 68%, respectively. Spontaneous ST-segment changes during daytime were recorded more often in patients with SCA (50%) and syncope (39%) than angina-only patients (4%, p0.01 for each). Nocturnal angina occurred less frequently in patients with SCA (33%) and syncope (32%) than angina-only patients (83%, p0.01 for each). Severe multivessel spasm, daytime ST-segment changes, and younger age were significant predictors of SCA. Daytime ST-segment changes and active smoking were related to syncope.The circadian variance of coronary spasm triggering SCA or syncope may be different from that inducing typical coronary spastic angina. The coronary spasm should be evaluated for patients with aborted SCA or recurrent syncope of unknown cause, even though the patients have not experienced the typical nocturnal angina.