Adding interactive face-to-face lectures to passive lectures effectively reduces radiation exposure during atrial fibrillation ablation.

BACKGROUND: Radiation exposure remains a major concern for electrophysiologists and patients. This study aimed to investigate the effect of altering awareness of radiation exposure during atrial fibrillation ablation using interactive face-to-face (FTF) lectures compared to passive lectures. METHODS: Patients who underwent their first catheter ablation with radiofrequency energy for atrial fibrillation between January 2014 and December 2020 were included in this study. All operators attended an e-learning lecture on radiation exposure before catheter ablation. The addition of FTF lectures to this lecture was introduced in 2018. The effect on radiation exposure was compared between the pre-FTF and FTF periods by comparing fluoroscopy time and radiation dose. RESULTS: A total of 896 patients [mean age, 66 ±â€¯11 years; 603 men (67 %)] were included in this study. For pre-FTF (n = 345), only pulmonary vein isolation (PVI) was performed in 112 patients and PVI with additional ablation in 233 patients. For FTF lectures (n = 551), PVI-only was performed in 302 patients and PVI with additional ablation in 249 patients. Fluoroscopy time, cumulative air kerma, and cumulative air kerma per time significantly reduced after FTF introduction in both PVI-only group [pre-FTF and FTF; 37 ±â€¯15 min and 16 ±â€¯10 min (p < 0.0001), 477 ±â€¯582 mGy and 108 ±â€¯156 mGy (p < 0.0001), 11 ±â€¯12 mGy/min, and 5 ±â€¯6 mGy/min (p < 0.0001), respectively] and PVI with additional ablation group [pre-FTF and FTF; 48 ±â€¯17 min and 15 ±â€¯13 min (p < 0.0001), 613 ±â€¯483 mGy and 68 ±â€¯96 mGy (p < 0.0001), 12 ±â€¯10 mGy/min, and 4 ±â€¯4 mGy/min (p < 0.0001), respectively]. There were no significant differences in intraoperative complications between the two periods. CONCLUSIONS: FTF lectures can reduce radiation exposure.

A multicenter prospective randomized study comparing the incidence of periprocedural cerebral embolisms caused by catheter ablation of atrial fibrillation between cryoballoon and radiofrequency ablation (Embo-Abl study): Study design.

BACKGROUND: Although catheter ablation (CA) has become a standard therapeutic approach to atrial fibrillation (AF), it imposes a low but relevant risk of thromboembolic complications of around 0.5%-1%, including ischemic strokes, and has an additional risk of clinically silent cerebral embolisms (SCEs) of 10%-40%. Both cryoballoon (CB) and radiofrequency (RF) ablation are routinely used clinically worldwide, yet there are few prospective data comparing the incidence of cerebral embolism after CA of AF between CB and RF ablation. METHODS: The aim of the Embo-Abl study will be to compare the incidence of cerebral embolisms on 3 T diffusion-weighted image magnetic resonance imaging (MRI) after CA of AF between CB and RF ablation in patients with AF in a prospective, multicenter, open-label, controlled, randomized fashion. The primary endpoint of the Embo-Abl study will be the occurrence of MRI-detected SCE 1-3 days after CA. The patients will be registered and randomly assigned to either the CB or RF ablation group in a 1:1 ratio. The study cohort will include 230 patients with AF from a multicenter in Japan. RESULTS: The results of this study are currently under investigation. CONCLUSION: The Embo-Abl study will be the first to compare the incidence of periprocedural cerebral embolisms caused by CA of AF between CB and RF ablation in a prospective, multicenter, randomized, controlled fashion.

Cerebrospinal fluid shunt for normal pressure hydrocephalus patient exacerbates cord symptoms due to spinal tumor.

Background: Normal-pressure hydrocephalus (NPH) and spinal intradural extramedullary benign tumors rarely exist together. Here, a 72-year-old female who presented with NPH symptoms (i.e., gait disturbance and dementia) newly developed symptoms of spinal cord compression attributed to a previously undiagnosed schwannoma. Case Description: A 72-year-old female was diagnosed with NPH without disproportionately enlarged subarachnoid space hydrocephalus. The lumbar puncture revealed an elevated cerebrospinal fluid (CSF) protein level of 0.141 g/dl, but with normal pressure. The patient's NPH symptoms improved after lumbar-peritoneal shunt placement. However, a year later, she subacutely developed a progressive Brown-Sequard syndrome. On the cervical magnetic resonance (MR), an intradural extramedullary lesion was found at the C5-C6 level which at surgery, proved to be a schwannoma. A review of this patient and three others with NPH and intradural extramedullary benign tumors revealed that 4.3 months following CSF shunting for NPH, they developed rapidly progressive cord deficits, attributed to their benign spinal tumors. Conclusion: Before the placement of shunts for NPH, patients should undergo holospinal MR imaging studies to rule out attendant spinal intradural extramedullary tumors.

Usefulness of criteria for intraoperative Management of Postoperative Nausea and Vomiting.

BACKGROUND: Postoperative nausea and vomiting (PONV) delays postoperative recovery, prolongs hospital stays, and hinders patients' return to society, thus making it a major cause of increased healthcare costs. It is also the most troubling postoperative complication in female patients undergoing surgery. However, in Japan, guidelines for the management of PONV have not been established, and the management protocol for PONV is left to each institution and anesthesiologist. Therefore, we developed criteria for intraoperative management of PONV. METHODS: In female surgical patients, the usefulness of the criteria was evaluated by comparing the implementation rate of intraoperative management and PONV incidence before and after the establishment of the criteria. An Apfel simplified score (Apfel score) ≥2 was set as an indication for intraoperative management of PONV. RESULTS: The implementation rate of intraoperative management increased from 91.2 to 96.0% after the introduction of the criteria. In patients with an Apfel score of 2, the intraoperative management implementation rate significantly increased from 81.1 to 94.7% (p = 0.016), while PONV incidence significantly decreased from 44.6 to 34.1% after the introduction of the criteria (p = 0.040). CONCLUSIONS: The criteria for intraoperative management of PONV increased the implementation rate of intraoperative management and decreased PONV incidence, indicating the usefulness of the criteria.

Impact of nocturnal hypoxemia on the recurrence of atrial tachyarrhythmia after catheter ablation of atrial fibrillation.

Factors causing atrial tachyarrhythmia recurrence after catheter ablation (CA) of atrial fibrillation (AF) remain undetermined. This study aimed to investigate the effect of nocturnal hypoxemia on the recurrence of atrial tachyarrhythmia after CA of AF. Among 594 patients with AF who underwent an ambulatory sleep study at the National Cerebral and Cardiovascular Center, Suita, Osaka, Japan (2014-2019), 365 underwent CA of AF; 290 patients who underwent CA were followed up for > 3 months. Multivariate Cox regression analysis was used to calculate hazard ratios (HRs) using clinical variables, to identify the independent predictors of atrial tachyarrhythmia recurrence after the final CA. Atrial tachyarrhythmia recurred in 45 of 290 (15.5%) patients during the median follow-up period of 479 days (interquartile range 225-1002). On the performing multivariate analysis of the data of patients who did not receive continuous positive airway pressure (CPAP), severe nocturnal hypoxemia [defined as the percentage of sleep time spent with SaO2 of < 90% (T90) over 20%] [HR 8.53, 95% confidence interval (CI) 1.872-38.814; P < 0.01] and an 1 mL/m2 increase in the left atrial volume index (HR 1.02, 95% CI 1.004-1.044; P = 0.02) were found to be independently associated with the recurrence of atrial tachyarrhythmia. In addition, the rates of freedom from atrial tachyarrhythmia after the final AF ablation with CPAP were significantly lower in the group with more severe nocturnal hypoxemia (Log-rank P = 0.03). In conclusion, it is necessary to consider both, AHI and nocturnal hypoxia while performing an ambulatory sleep apnea study. CA may be less effective in patients with more severe nocturnal hypoxia, despite the administration of CPAP.

GP96 Drives Exacerbation of Secondary Bacterial Pneumonia following Influenza A Virus Infection.

Influenza A virus (IAV) infection predisposes the host to secondary bacterial pneumonia, known as a major cause of morbidity and mortality during influenza virus epidemics. Analysis of interactions between IAV-infected human epithelial cells and Streptococcus pneumoniae revealed that infected cells ectopically exhibited the endoplasmic reticulum chaperone glycoprotein 96 (GP96) on the surface. Importantly, efficient pneumococcal adherence to epithelial cells was imparted by interactions with extracellular GP96 and integrin αV, with the surface expression mediated by GP96 chaperone activity. Furthermore, abrogation of adherence was gained by chemical inhibition or genetic knockout of GP96 as well as addition of RGD peptide, an inhibitor of integrin-ligand interactions. Direct binding of extracellular GP96 and pneumococci was shown to be mediated by pneumococcal oligopeptide permease components. Additionally, IAV infection induced activation of calpains and Snail1, which are responsible for degradation and transcriptional repression of junctional proteins in the host, respectively, indicating increased bacterial translocation across the epithelial barrier. Notably, treatment of IAV-infected mice with the GP96 inhibitor enhanced pneumococcal clearance from lung tissues and ameliorated lung pathology. Taken together, the present findings indicate a viral-bacterial synergy in relation to disease progression and suggest a paradigm for developing novel therapeutic strategies tailored to inhibit pneumococcal colonization in an IAV-infected respiratory tract. IMPORTANCE Secondary bacterial pneumonia following an influenza A virus (IAV) infection is a major cause of morbidity and mortality. Although it is generally accepted that preceding IAV infection leads to increased susceptibility to secondary bacterial infection, details regarding the pathogenic mechanism during the early stage of superinfection remain elusive. Here, we focused on the interaction of IAV-infected cells and Streptococcus pneumoniae, which revealed that human epithelial cells infected with IAV exhibit a cell surface display of GP96, an endoplasmic reticulum chaperon. Notably, extracellular GP96 was shown to impart efficient adherence for secondary infection by S. pneumoniae, and GP96 inhibition ameliorated lung pathology of superinfected mice, indicating it to be a useful target for development of therapeutic strategies for patients with superinfection.

Relationship between electrical gaps after Maze procedure and atrial tachyarrhythmias and ablation outcomes after cardiac surgery and concomitant Maze procedure.

Atrial tachycardia (AT) and atrial fibrillation (AF) commonly occur after cardiac surgeries (CSs). This study investigated the mechanisms and long-term outcomes of AT and AF ablation after various Maze procedures, particularly whether atrial tachyarrhythmias after the Maze procedure occur due to gaps in the Maze lines. We analyzed 37 consecutive cases with atrial tachyarrhythmias after the Maze procedures and concomitant CSs between 2007 and 2019. Fifty-nine atrial tachyarrhythmias were induced in 37 consecutive cases, and 49 of those atrial tachyarrhythmias were mappable ATs. Forty ATs were related to the Maze procedures in the 49 mappable ATs (81.6%). All 37 consecutive cases had residual electrical conductions (gaps) in the Maze lines (88 gaps; 2.4 ± 1.2 gaps/patient). Forty of 88 gaps (45.5%) were associated with gap-related ATs. The common ATs in this study were 1. peri-mitral atrial flutter due to gaps at pulmonary vein isolation (PVI) line to mitral valve annulus (MVA) (20 cases), and 2. peri-tricuspid atrial flutter due to gaps at right atrial incision to the tricuspid valve annulus (TVA) (10 cases). Forty-seven of 49 ATs (95.9%) were successfully ablated at the first session, and there were no complications. The mean follow-up period after ablation was 3.6 ± 3.2 (median, 2.1; interquartile range, 0.89-6.84) years. The Kaplan-Meier analysis of freedom from recurrent atrial tachyarrhythmias after Maze procedure was 82.7% at 1-year follow-up and 75.5% at 4-year follow-up after a single procedure. Reentry was the main mechanism of ATs after Maze procedures and concomitant CSs, and ATs were largely related to the gaps on the Maze lines between the PVI line and the MVA or those on the lines between right atrial incision to the TVA. Long-term follow-up data suggest that catheter ablation of atrial tachyarrhythmias after various Maze procedures is effective and safe.

Prognosis and Outcomes of Clinically Diagnosed Cardiac Sarcoidosis Without Positive Endomyocardial Biopsy Findings.

Background: Diagnosis of cardiac sarcoidosis (CS) is sometimes difficult due to a low positive rate of epithelioid granulomas by endomyocardial biopsy (EMB). Accordingly, Japanese guidelines can allow the CS diagnosis using clinical data alone without EMB results (clinical CS) since 2006. However, little is known about prognosis and outcome of clinical CS. Objectives: Purpose of this study was to analyze the prognosis, outcomes, and response to corticosteroid of clinical CS using large-scale cohort survey. Methods: Overall, 422 CS patients (mean age 60 ± 13 years, 68% female, median follow-up period of 5 years), including 345 clinical CS and 77 EMB-positive patients, histologically diagnosed CS (histological CS) by Japanese guidelines, were enrolled and examined. Results: Clinical profile (age, sex, initial cardiac arrhythmias, and abnormal uptake of gallium-67 scintigraphy or 18F-fluorodeoxyglucose positron emission tomography in heart) was similar in both groups. Although clinical CS had better prognosis (P = 0.018) and outcome (all-cause death, appropriate defibrillator therapy, and heart transplantation; P = 0.008), multivariate Cox hazard analysis revealed that left ventricular ejection fraction (LVEF) and sustained ventricular tachycardia history were independently associated with outcome (P < 0.001 and P = 0.002, respectively), but not with the diagnosed CS category. Moreover, similar LVEF recovery after corticosteroid was observed in both groups with low LVEF (≤35%) at the 1-year follow-up period (P < 0.001). Conclusions: In clinical CS according to the Japanese guideline, prophylactic implantable-cardioverter-defibrillator and immunosuppressive therapy are important in patients with low LVEF or ventricular tachycardia history, similar to histological CS.

Transcatheter cryo-ablation of septal accessory pathways, multicenter observational study in Japan.

BACKGROUND: Ablation using radiofrequency energy has to be carefully performed when the arrhythmia substrate is located in close proximity to the atrioventricular (AV) node due to the risk of inadvertent permanent AV block. The aim of this study was to evaluate the efficacy and safety of catheter-based cryo-therapy for septal accessory pathways (APs). METHODS: A total of eleven patients (median = 56.3 years, range 13-74 years) with septal APs underwent cryoablation. Ice-mapping was performed during sinus rhythm and an AV reciprocating tachycardia utilizing the APs as a requisite limb with cooling of the catheter tip temperature to a maximum of -30℃ for less than 45 s. Cryo-ablation was performed for 4 min at a temperature of -80℃ only if ice-mapping abolished the pre-excitation or retrograde conduction over the AP without injury to the AV nodal conduction. RESULTS: Cryo-ablation was acutely successful in all eleven patients. No permanent cryo-related complications or adverse outcomes were reported. During the follow-up (range 14-26 months), no patients experienced any arrhythmia recurrences. CONCLUSION: Ice-mapping was a feasible and reliable method to determine the exact location of the APs owing to the possibility of validating the ablation site. Cryo-ablation of APs located near the AV junction is a safe and efficacious technique with a high success rate over the long term. IRB INFORMATION: Ethical Committee of Japan Red Cross Yokohama City Bay Hospital #2018-19.

Subcutaneous and transvenous implantable cardioverter defibrillator in high-risk long-QT syndrome type 3 associated with Val411Met mutation in SCN5A.

Congenital long-QT syndrome type 3 (LQT3) with SCN5A-V411M mutation has been reported as a malignant case of LQT3 with highest risk for sudden cardiac death (SCD). Here, we present two cases of LQT3 with SCN5A-V411M who had been implanted with subcutaneous (S-) or transvenous (TV-) implantable cardioverter defibrillators (ICD). Case 1, a 2-year-old boy, although he had no symptoms, was diagnosed as having LQT3 (V411M-SCN5A) due to family history. The QTc interval was still longer than 500 ms during follow-up even under oral mexiletine. Case 2 (his aunt) diagnosed as LQT3 suffered from syncope caused by ventricular fibrillation at 35-years-old despite taking mexiletine. Furthermore, case 1's father and half-brother, both had the V411M mutation with LQT3, had suddenly died. Thus, case 1 was recommended S-ICD when he was 15-years-old for primary prevention of SCD but not necessary for pacing therapy, while, case 2 had been implanted TV-ICD for secondary prevention of SCD. They had no event after ICD implantation, however, case 2 had to have added an extra ICD-lead due to lead failure when she was 44-years-old. The S-ICD may be a potent therapeutic option for high-risk LQTS when patients are younger and do not need pacing therapy. .

Identification of malignant early repolarization pattern by late QRS activity in high-resolution magnetocardiography.

BACKGROUND: The early repolarization pattern (ERP) in electrocardiography (ECG) has been considered as a risk for ventricular fibrillation (VF), but effective methods for identification of malignant ERP are still required. We investigated whether high spatiotemporal resolution 64-channel magnetocardiography (MCG) would enable distinction between benign and malignant ERPs. METHODS: Among all 2,636 subjects who received MCG in our facility, we identified 116 subjects (43 ± 18 years old, 54% male) with inferior and/or lateral ERP in ECG and without structural heart disease, including 13 survivors of VF (ERP-VF(+)) and 103 with no history of VF (ERP-VF(-)). We measured the following MCG parameters in a time-domain waveform of relative current magnitude: (a) QRS duration (MCG-QRSD), (b) root-mean-square of the last 40 ms (MCG-RMS40), and (c) low amplitude (<10% of maximal) signal duration (MCG-LAS). RESULTS: Compared to ERP-VF(-), ERP-VF(+) subjects presented a significantly longer MCG-QRS (108 ± 24 vs. 91 ± 23 ms, p = .02) and lower MCG-RMS40 (0.10 ± 0.08 vs. 0.25 ± 0.20, p = .01) but no difference in MCG-LAS (38 ± 22 vs. 29 ± 23 ms, p = .17). MCG-QRSD and MCG-RMS40 showed significantly larger area under the ROC curve compared to J-peak amplitude in ECG (0.72 and 0.71 vs. 0.50; p = .04 and 0.03). The sensitivity, specificity, and odds ratio for identifying VF(+) based on MCG-QRSD ≥ 100 ms and MCG-RMS40 ≤ 0.24 were 69%, 74%, and 6.33 (95% CI, 1.80-22.3), and 92%, 48%, and 10.9 (95% CI, 1.37-86.8), respectively. CONCLUSION: Magnetocardiography is an effective tool to distinguish malignant and benign ERPs.

Therapeutic and Adverse Effects of Thrombomodulin Alfa to Treat Sepsis-Induced Disseminated Intravascular Coagulation.

In the treatment of disseminated intravascular coagulation (DIC), which is a complication of underlying diseases such as infections and malignant tumors, effective plasma concentrations of thrombomodulin (TM) alfa range from 300 to 900 ng/mL; however, appropriate concentrations when treating sepsis-induced DIC are unknown. Thus, our aim was to determine the relationship between plasma concentrations of TM alfa and its therapeutic effects, and hemorrhagic adverse events. First, we calculated the plasma trough concentrations of TM alfa in septic DIC patients. Next, we divided patients into two groups according to their plasma concentrations into a low- and high-concentration group based on a cut-off value of 600 ng/mL. Fourteen and 35 patients were included in the low- and high-concentration groups, respectively. The Japanese Association for Acute Medicine DIC diagnostic criteria score 4 days after TM alfa administration decreased significantly by 2.06 points from baseline in the high-concentration group compared with 0.71 points in the low-concentration group. The 90-day survival rate was significantly higher in the high-concentration group (85.4%) than in the low-concentration group (49.0%) (hazard ratio, 0.27; 95% confidence interval: 0.09-0.86). In contrast, the incidence of serious hemorrhage was not significantly different between the groups. The recommended plasma concentration of TM alfa in the treatment of septic DIC was determined to be higher than 600 ng/mL, and a dose of 380 U/kg (0.06 mg/kg) was necessary to achieve this concentration.

Clinical Differences in Japanese Patients Between Brugada Syndrome and Arrhythmogenic Right Ventricular Cardiomyopathy With Long-Term Follow-Up.

Some Brugada syndrome (BrS) patients have been suspected of being in the initial state of arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aimed to clarify the electrocardiographic (ECG) and clinical differences between BrS and ARVC in long-term follow-up (mean 11.9 ± 6.3 years). A total of 50 BrS and 65 ARVC patients with fatal ventricular tachyarrhythmia (VTA) were evaluated according to the revised Task Force Criteria for ARVC. Based on the current diagnostic criteria concerning electrocardiographic, repolarization abnormality was positive in 2.0% and 2.6% of BrS patients at baseline and follow-up, and depolarization abnormality was positive in 6.0% and 12.8% of BrS patients at baseline and follow-up, respectively. At baseline, none of the BrS patients were definitively diagnosed with ARVC. Considering patients' lives since birth, Kaplan-Meier analysis revealed that age at first VTA attack showed the same tendency between the groups (BrS: mean 42.2 ± 12.5 years old vs ARVC: mean 44.8 ± 13.7 years old, log-rank p = 0.123). Moreover, the incidence of VTA recurrence was similar between the groups during follow-up (log-rank p = 0.906). Incidence of sustained monomorphic ventricular tachycardia was significantly higher in ARVC than in BrS whereas the opposite was true for ventricular fibrillation (log-rank p <0.001 and p <0.001, respectively). None of the diagnoses of BrS patients were changed to ARVC during follow-up. During long-term follow-up, although age at first VTA attack and VTA recurrence were similar, BrS consistently exhibited features that differed from those of ARVC.

Multicenter Study of the Validity of Additional Freeze Cycles for Cryoballoon Ablation in Patients With Paroxysmal Atrial Fibrillation: The AD-Balloon Study.

BACKGROUND: Pulmonary vein isolation (PVI) is a cornerstone of catheter ablation in patients with paroxysmal atrial fibrillation, and balloon-based ablation has been recently performed worldwide. The second-generation cryoballoon (CB2) ablation has proven to be highly effective in achieving freedom from paroxysmal atrial fibrillation. However, there are some debatable questions, including the ideal number of freeze cycles. METHODS: The AD-Balloon study (Multicenter Study of the Validity of Additional Freeze Cycles for Cryoballoon Ablation) was designed as a prospective, multicenter, and randomized clinical trial for investigation of the optimal strategy of freeze cycles for the CB2 ablation. One hundred and ten consecutive patients (aged 64±11 years) were randomly assigned to 2 groups after achieving a PVI by the CB2 ablation: 3-minute freeze cycles were added to each pulmonary vein (AD group: n=55) or not (non-AD group: n=55). Delayed-enhancement magnetic resonance imaging was also performed 1 to 2 months after the PVI to assess the ablation lesions. RESULTS: The patient characteristics did not differ between the 2 groups. A complete PVI was achieved in all patients. The total number of freeze cycles and durations for all pulmonary veins were significantly shorter in the non-AD group than in the AD group (5.7±1.6 versus 9.1±1.6 cycles, P<0.0001, and 932±244 versus 1483±252 seconds, P<0.0001). The cumulative freedom from any atrial tachyarrhythmia at 1 year was 87.3% in the AD group and 89.1% in the non-AD group (log-rank test P=0.78). There was no significant difference in the frequency of gaps on the PVI lines in the delayed-enhancement magnetic resonance imaging (46% in the AD group versus 36% in the non-AD group; P=0.38). CONCLUSIONS: No benefit was found in the patients receiving additional 3-minute freeze cycles after the complete PVI with the CB2 ablation, suggesting that an insurance freeze after achieving a PVI with the CB2 may be unnecessary and time consuming.

HCN4-Overexpressing Mouse Embryonic Stem Cell-Derived Cardiomyocytes Generate a New Rapid Rhythm in Rats with Bradycardia.

A biological pacemaker is expected to solve the persisting problems of an artificial cardiac pacemaker including short battery life, lead breaks, infection, and electromagnetic interference. We previously reported HCN4 overexpression enhances pacemaking ability of mouse embryonic stem cell-derived cardiomyocytes (mESC-CMs) in vitro. However, the effect of these cells on bradycardia in vivo has remained unclear. Therefore, we transplanted HCN4-overexpressing mESC-CMs into bradycardia model animals and investigated whether they could function as a biological pacemaker. The rabbit Hcn4 gene was transfected into mouse embryonic stem cells and induced HCN4-overexpressing mESC-CMs. Non-cardiomyocytes were removed under serum/glucose-free and lactate-supplemented conditions. Cardiac balls containing 5 × 103 mESC-CMs were made by using the hanging drop method. One hundred cardiac balls were injected into the left ventricular free wall of complete atrioventricular block (CAVB) model rats. Heart beats were evaluated using an implantable telemetry system 7 to 30 days after cell transplantation. The result showed that ectopic ventricular beats that were faster than the intrinsic escape rhythm were often observed in CAVB model rats transplanted with HCN4-overexpressing mESC-CMs. On the other hand, the rats transplanted with non-overexpressing mESC-CMs showed sporadic single premature ventricular contraction but not sustained ectopic ventricular rhythms. These results indicated that HCN4-overexpressing mESC-CMs produce rapid ectopic ventricular rhythms as a biological pacemaker.

Pathogenic mechanisms of invasive group A Streptococcus infections by influenza virus-group A Streptococcus superinfection.

Group A Streptococcus (GAS) are pathogenic bacteria of the genus Streptococcus and cause severe invasive infections that comprise a wide range of diverse diseases, including acute respiratory distress syndrome, renal failure, toxic shock-like syndrome, sepsis, cellulitis and necrotizing fasciitis. The essential virulence, infected host and external environmental factors required for invasive GAS infections have not yet been determined. Superinfection with influenza virus and GAS induced invasive GAS infections was demonstrated by our team in a mouse model, after which clinical cases of invasive GAS infections secondary to influenza virus infection were reported by other investigators in Japan, USA, Canada, UK China, and other countries. However, the pathogenic mechanisms underlying influenza virus-GAS superinfection are not yet fully understood. The present review describes the current knowledge about invasive GAS infections by superinfection. Topics addressed include the bacteriological, virological and immunological mechanisms impacting invasion upon superinfection on top of underlying influenza virus infection by GAS and other bacteria (i.e., Streptococcus pneumoniae and Staphylococcus aureus). Future prospects are also discussed.

Isolated Late Activation Detected by Magnetocardiography Predicts Future Lethal Ventricular Arrhythmic Events in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy.

BACKGROUND: Risk stratification of ventricular arrhythmias is vital to the optimal management in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). We hypothesized that 64-channel magnetocardiography (MCG) would be useful to detect isolated late activation (ILA) by overcoming the limitations of conventional noninvasive predictors of ventricular tachyarrhythmias, including epsilon waves, late potential (LP), and right ventricular ejection fraction (RVEF), in ARVC patients.Methods and Results:We evaluated ILA on MCG, defined as discrete activations re-emerging after the decay of main RV activation (%magnitude >5%), and conventional noninvasive predictors of ventricular tachyarrhythmias (epsilon waves, LP, and RVEF) in 40 patients with ARVC. ILA was noted in 24 (60%) patients. Most ILAs were found in RV lateral or inferior areas (17/24, 71%). We defined "delayed ILA" as ILA in which the conduction delay exceeded its median (50 ms). During a median follow-up of 42.5 months, major arrhythmic events (MAEs: 1 sudden cardiac death, 3 sustained ventricular tachycardias, and 4 appropriate implantable cardioverter defibrillator discharges) occurred more frequently in patients with delayed ILA (6/12) than in those without (2/28; log-rank: P=0.004). Cox regression analysis identified delayed ILA as the only independent predictor of MAEs (hazard ratio 7.63, 95% confidence interval 1.72-52.6, P=0.007), and other noninvasive parameters were not significant predictors. CONCLUSIONS: MCG is useful to identify ARVC patients at high risk of future lethal ventricular arrhythmias.

Heart failure in patients with arrhythmogenic right ventricular cardiomyopathy: What are the risk factors?

BACKGROUND: We previously demonstrated that heart failure (HF) was one of the major causes of death in arrhythmogenic right ventricular cardiomyopathy (ARVC). The purpose of this study was to elucidate the clinical impact and risk factors of HF in patients with ARVC. METHODS AND RESULTS: We evaluated cardiac adverse outcomes including HF in 113 consecutive patients with ARVC (85 men, mean age: 44±15years). During a median follow-up of 10.0years (interquartile range: 5.2 to 15.7years), 29 patients (26%) were hospitalized for progressive HF. The patients with one or more episodes of HF hospitalization had about a 10-fold increased incidence of cardiac death (14/29 [48%] vs. 4/84 [4.7%], p<0.0001). Left ventricular ejection fraction (LVEF) and right ventricular ejection fraction (RVEF) were significantly lower in the patients with HF hospitalization compared to the patients without HF hospitalization (LVEF, 45±15 vs. 54±13%, p=0.001; RVEF, 26±10 vs. 33±11%, p=0.003, respectively). Regarding the ECG findings, the prevalence of first-degree atrioventricular block (AVB, PR interval >200ms) and epsilon waves were significantly higher in patients with HF hospitalization than those without HF hospitalization (first-degree AVB, 14/29 [48%] vs. 11/84 [13%], p<0.0001; epsilon waves, 10/29 [34%] vs. 12/84 [14%], p=0.02). In multivariate analysis, first-degree AVB at baseline was the strongest independent risk factor for HF hospitalization in patients with ARVC (hazard ratio 4.24, 95% confidence interval 1.79-10.47, p=0.0011). CONCLUSION: HF hospitalization has a significant relation with malignant clinical course in ARVC patients. First-degree AVB was an independent determinant for increased risk of HF hospitalization.

[Comparison of the Cost-Effectiveness of the SOX and COX Regimens in Patients with Unresectable Advanced and Recurrent Colorectal Cancer Using a Clinical Decision Analysis Approach].

Phase III clinical trials have comfirmed that the S-1 plus oxaliplatin(SOX)is inferior to the capecitabine plus oxaliplatin (COX)regimen in the treatment of metastatic colorectal cancer.On the basis of these findings, we compared, using a clinical decision analysis-based approach, the cost-effectiveness of the SOX and COX regimens.Herein, we simulated the expected effects and costs of the SOX and COX regimens using the markov model.Clinical data were obtained from Hong's 2012 report.The cost data comprised the costs for pharmacist labor, material, inspection, and treatment for adverse event, as well as the total cost of care at the advanced stage.The result showed that the expected cost of the SOX and COX regimen was 1,538,330 yen, and 1,429,596 yen, respectively, with an expected survival rate of 29.18 months, and 28.63 months, respectively.The incremental cost-effectiveness ratio of the SOX regimen was 197,698 yen/month; thus, the SOX regimen was found to be more cost-effective that the COX regimen.