ER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P.

Nonalcoholic fatty liver disease (NAFLD) progresses to nonalcoholic steatohepatitis (NASH) in response to elevated endoplasmic reticulum (ER) stress. Whereas the onset of simple steatosis requires elevated de novo lipogenesis, progression to NASH is triggered by accumulation of hepatocyte-free cholesterol. We now show that caspase-2, whose expression is ER-stress inducible and elevated in human and mouse NASH, controls the buildup of hepatic-free cholesterol and triglycerides by activating sterol regulatory element-binding proteins (SREBP) in a manner refractory to feedback inhibition. Caspase-2 colocalizes with site 1 protease (S1P) and cleaves it to generate a soluble active fragment that initiates SCAP-independent SREBP1/2 activation in the ER. Caspase-2 ablation or pharmacological inhibition prevents diet-induced steatosis and NASH progression in ER-stress-prone mice. Caspase-2 inhibition offers a specific and effective strategy for preventing or treating stress-driven fatty liver diseases, whereas caspase-2-generated S1P proteolytic fragments, which enter the secretory pathway, are potential NASH biomarkers.

The impact of early cryoballoon ablation on clinical outcome in patients with atrial fibrillation: From the Korean cryoballoon ablation registry.

INTRODUCTION: Influence of early atrial fibrillation (AF) ablation, particularly cryoballoon ablation (CBA), on clinical outcome during long-term follow-up has not been clarified. The objective was to determine whether an early CBA (diagnosis-to-ablation of ≤6 months) strategy could affect freedom from AF recurrence after index CBA. METHODS: The study included 2605 patients from Korean CBA registry data with follow-up >12 months after de novo CBA. The primary outcome was recurrence of atrial tachyarrhythmias (ATs) of ≥30-s after a 3-month blanking period. RESULTS: Compared to patients in early CBA group, patients in late CBA group had higher prevalence of diabetes, congestive heart failure, and chronic kidney disease, and higher mean CHA2 DS2 -VAS score. During mean follow-up of >21 months, ATs recurrence was detected in 839 (32.2%) patients. The early CBA group showed a significantly lower 2-year recurrence rate of ATs than the late CBA group (26.1% vs. 31.7%, p = 0.043). In subgroup analysis, the early CBA group showed significantly higher 1-year and 2-year freedom from ATs recurrence than the late CBA group only in paroxysmal atrial fibrillation (PAF) patients in overall and propensity score matched cohorts. Multivariate analysis showed that early CBA was an independent factor for preventing ATs recurrence in PAF (hazard ratio: 0.637; 95% confidence intervals: 0.412-0.984). CONCLUSION: Early CBA strategy, resulting in significantly lower ATs recurrence during 2-year follow-up after index CBA, might be considered as an initial rhythm control therapy in patients with paroxysmal AF.

Long-term clinical impact of early recurrence of atrial tachyarrhythmia after cryoballoon ablation in patients with atrial fibrillation.

INTRODUCTION: The impact of early recurrence of atrial tachyarrhythmia (ERAT) within the 90-day blanking period on long-term outcomes in atrial fibrillation (AF) patients undergoing cryoballoon ablation (CBA) is controversial. This study aimed to assess the relationship between ERAT and late recurrence of atrial tachyarrhythmia (LRAT) post-CBA. METHODS: Utilizing data from a multicenter registry in Korea (May 2018 to June 2022), we analyzed the presence and timing of ERAT (<30, 30-60, and 60-90 days) and its association with LRAT risk after CBA. LRAT was defined as any recurrence of AF, atrial flutter, or atrial tachycardia lasting more than 30 s beyond the 90 days. RESULTS: Out of 2636 patients, 745 (28.2%) experienced ERAT post-CBA. Over an average follow-up period of 21.2 ± 10.3 months, LRAT was observed in 874 (33.1%) patients. Patients with ERAT had significantly lower 1-year LRAT freedom compared to those without ERAT (42.6% vs. 85.5%, p < .001). Multivariate analysis identified ERAT as a potential predictor of LRAT, with a hazard ratio (HR) of 3.98 (95% confidence interval [CI], 3.47-4.57). Significant associations were noted across all examined time frames (HR, 3.84; 95% CI, 3.32-4.45 in <30 days, HR, 5.53; 95% CI, 4.13-7.42 in 30-60 days, and HR, 4.29; 95% CI, 3.12-5.89 in 60-90 days). This finding was consistently observed across all types of AF. CONCLUSION: ERAT during the 90-day blanking period strongly predicts LRAT in AF patients undergoing CBA, indicating a need to reconsider the clinical significance of this period.

Association between body mass index and results of cryoballoon ablation in Korean patients with atrial fibrillation: an analysis from the Korean Heart Rhythm Society Cryoablation registry.

AIMS: Pulmonary vein isolation using cryoablation is effective and safe in patients with atrial fibrillation (AF). Although both obesity and underweight are associated with a higher risk for incident AF, there is limited data on the efficacy and safety following cryoablation according to body mass index (BMI) especially in Asians. METHODS AND RESULTS: Using the Korean Heart Rhythm Society Cryoablation registry, a multicentre registry of 12 tertiary hospitals, we analysed AF recurrence and procedure-related complications after cryoablation by BMI (kg/m2) groups (BMI < 18.5, underweight, UW; 18.5-23, normal, NW; 23-25, overweight, OW; 25-30, obese Ⅰ, OⅠ; ≥30, obese Ⅱ, OⅡ). A total of 2648 patients were included (median age 62.0 years; 76.7% men; 55.6% non-paroxysmal AF). Patients were categorized by BMI groups: 0.9% UW, 18.7% NW, 24.8% OW, 46.1% OI, and 9.4% OII. Underweight patients were the oldest and had least percentage of non-paroxysmal AF (33.3%). During a median follow-up of 1.7 years, atrial arrhythmia recurred in 874 (33.0%) patients (incidence rate, 18.9 per 100 person-years). After multivariable adjustment, the risk of AF recurrence was higher in UW group compared with NW group (adjusted hazard ratio, 95% confidence interval; 2.55, 1.18-5.50, P = 0.02). Procedure-related complications occurred in 123 (4.7%) patients, and the risk was higher for UW patients (odds ratio, 95% confidence interval; 2.90, 0.94-8.99, P = 0.07), mainly due to transient phrenic nerve palsy. CONCLUSION: Underweight patients showed a higher risk of AF recurrence after cryoablation compared with NW patients. Also, careful attention is needed on the occurrence of phrenic nerve palsy in UW patients.

Comparison of High- and Low-Dose Rivaroxaban Regimens in Elderly East Asian Patients With Atrial Fibrillation.

BACKGROUND: In the Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, rivaroxaban 20 mg was the on-label dose, and the dose-reduction criterion for rivaroxaban was a creatinine clearance of < 50 mL/min. Some Asian countries are using reduced doses label according to the J-ROCKET AF trial. The aim of this study was to assess the safety and efficacy of a high-dose rivaroxaban regimen (HDRR, 20/15 mg) and low-dose rivaroxaban regimen (LDRR, 15/10 mg) among elderly East Asian patients with atrial fibrillation (AF) in real-world practice. METHODS: This study was a multicenter, prospective, non-interventional observational study designed to evaluate the efficacy and safety of rivaroxaban in AF patients > 65 years of age with or without renal impairment. RESULTS: A total of 1,093 patients (mean age, 72.8 ± 5.8 years; 686 [62.9%] men) were included in the analysis, with 493 patients allocated to the HDRR group and 598 patients allocated to the LDRR group. A total of 765 patients received 15 mg of rivaroxaban (203 in the HDRR group and 562 in the LDRR group). There were no significant differences in the incidence rates of major bleeding (adjusted hazard ratio [HR], 0.64; 95% confidential interval [CI], 0.21-1.93), stroke (adjusted HR, 3.21; 95% CI, 0.54-19.03), and composite outcomes (adjusted HR, 1.13; 95% CI, 0.47-2.69) between the HDRR and LDRR groups. CONCLUSION: This study revealed the safety and effectiveness of either dose regimen of rivaroxaban in an Asian population for stroke prevention of AF. Considerable numbers of patients are receiving LDRR therapy in real-world practice in Asia. Both regimens were safe and effective for these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04096547.

Long-term outcome of thoracoscopic ablation and radiofrequency catheter ablation for persistent atrial fibrillation as a de novo procedure.

AIMS: Limited data are available regarding the efficacy of thoracoscopic ablation as the first procedure for persistent atrial fibrillation (AF). We sought to compare the long-term efficacy of thoracoscopic ablation vs. radiofrequency (RF) catheter ablation as the first procedure for persistent AF. METHODS AND RESULTS: Between February 2011 and December 2020, 575 patients who underwent ablation for persistent AF were studied. Among them, thoracoscopic ablation was performed in 281 patients, RF catheter ablation in 228, and hybrid ablation in 66. Rhythm, clinical, and safety outcomes during 7-year follow-up were compared. The patients who underwent thoracoscopic ablation were older, had a higher prevalence of stroke, and had a larger left atrial volume than those who underwent RF catheter ablation. In the propensity score-matched population (n = 306), incidences of atrial tachyarrhythmia recurrence were 51.4% in the thoracoscopic ablation group and 62.5% in the RF catheter ablation group [adjusted hazard ratio (HR) 0.869, 95% confidence interval (CI) 0.618-1.223, P = 0.420]. Stroke and total procedural adverse events were not significantly different between thoracoscopic and RF catheter ablation (2.7 vs. 2.5%, P = 0.603, and 7.1 vs. 4.8%, P = 0.374, respectively). The hybrid ablation group showed similar rhythm outcomes compared with both the thoracoscopic and the RF catheter ablation groups. At the redo procedure, pulmonary vein gaps were more frequently observed in the RF catheter ablation group (32.6%) than in the thoracoscopic ablation group (7.9%) and in the hybrid ablation group (8.8%) (P < 0.001). CONCLUSION: As a first procedure in persistent AF, thoracoscopic ablation and RF catheter ablation showed comparable efficacy, clinical, and safety outcomes during long-term follow-up.

Totally Thoracoscopic Ablation in Patients With Recurrent Atrial Fibrillation After Catheter Ablation.

BACKGROUND: The objective of this study was to evaluate the efficacy and safety of totally thoracoscopic ablation (TTA) in patients with recurrent atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA). METHODS: From February 2012 to May 2020, 460 patients who underwent TTA were classified into two groups: CA (presence of RFCA history, n = 74) and nCA groups (absence of RFCA history, n = 386). Inverse probability of treatment weighting (IPTW) analyses were used to adjust for confounders. The primary endpoint was freedom from the composite of AF, typical atrial flutter, atypical atrial flutter and any atrial tachyarrhythmia, lasting more than 30 seconds during the follow-up. All patients were followed up at 3, 6, and 12 months via electrocardiogram and 24-hour Holter monitoring. RESULTS: Bilateral pulmonary vein isolation (PVI) was conducted in all patients and the conduction block tests were confirmed. In the CA group, difficult PVI occasionally occurred due to structural changes, such as pericardial adhesion and fibrosis of the pulmonary venous structure, caused by a previous catheter ablation. Early complications such as stroke and pacemaker insertion were not different between the two groups. The normal sinus rhythm was maintained in 70.1% (317/460) patients after a median follow-up period of 38.1 months. The IPTW-weighted Kaplan-Meier curves revealed that freedom from AF events at 5 years was 68.4% (95% confidence interval, 62.8-74.5) in the nCA group and 31.2% (95% confidence interval, 16.9-57.5) in the CA group (P < 0.001). In IPTW-weighted Cox regression, preoperative left atrial diameter, persistent or long-standing AF, the presence of congestive heart failure and catheter ablation history were associated with AF events. CONCLUSION: Patients in the CA group showed a higher recurrence rate of AF than those in the nCA group, while TTA was safely performed in both the groups.

The efficacy of single-lead implantable cardioverter-defibrillator with atrial sensing dipole to detect atrial fibrillation and to reduce inappropriate therapy according to atrial sensing ON or OFF: Rationale and design of the SMART-CONTROL study, a prospective multicenter randomized trial.

BACKGROUND: Few studies have compared the efficacy of single-lead implantable cardioverter-defibrillator (ICD) with atrial sensing dipole (VDD-ICD) and conventional single-chamber ICD from the aspect of atrial fibrillation (AF) detection or inappropriate ICD therapy reduction. In the SMART-CONTROL trial (NCT03932604), we primarily aim to investigate whether the atrial sensing capability of VDD-ICD is useful in AF detection and inappropriate therapy reduction by randomly activating or deactivating the atrial sensing function. METHODS AND DESIGN: This study was designed as a prospective, multicenter, open-label, randomized trial to enroll 640 patients with no history of clinical AF or rhythm control for AF within 1 year who were undergoing the implantation of VDD-ICD system. Patients are assigned randomly to atrial sensing "ON" or "OFF" group, with crossover allowed during follow-up. The coprimary outcomes are the incidence of AF detection and inappropriate ICD therapy over a 2-year follow-up period. The secondary outcomes include non-AF atrial tachyarrhythmia, ventricular tachyarrhythmia with or without ICD therapy, thromboembolic events, bleeding, heart failure hospitalization, mortality, a composite of adverse cardiovascular events, and long-term atrial sensing stability or variability. CONCLUSION: We expect that this trial can evaluate the efficacy of a single-lead ICD system on various clinical outcomes including AF detection and inappropriate therapy reduction, and ultimately provide guidance to selection of ICD system.

Risk of infective endocarditis associated with invasive dental procedures in patients with cardiac rhythm devices.

AIMS: The incidence of infective endocarditis related to cardiac implantable electronic devices (CIEDs) has gradually increased. The risk associated with dental procedures in patients with CIED implantation and the need for prevention of infective endocarditis remain unclear. The present study investigated the incidence and risk of infective endocarditis associated with invasive dental procedures in patients with CIEDs. METHODS AND RESULTS: We analysed a nationwide population-based cohort of patients with CIEDs who underwent dental procedures. We performed a self-controlled case series analysis and evaluated the incidence rate ratio of infective endocarditis 3 months after dental procedures. Of a total of 62 019 patients who underwent CIED implantation, 32 536 patients underwent at least one dental procedure during follow-up, and the mean number of dental procedures was 3.4 per patient. They were 152 infections with an incidence of 445 per 100 000 person-years in the dental procedure period and 500 events at an incidence of 255 per 100 000 person-years in the non-dental procedure period. The CIED-related infective endocarditis in the dental procedure period occurred significantly more frequently than during non-dental procedure periods (odds ratio, 1.75; 95% confidence interval, 1.48-2.05; P < 0.001). The mean time interval from dental procedure to infective endocarditis was 59.6 ± 47.3 days. CONCLUSION: Invasive dental procedures are associated with an increased risk of infective endocarditis in those who underwent CIED implantation. Appropriate preventive therapy might be needed in these patients.

Outcomes of On-Label Reduced-Dose Edoxaban in Patients With Atrial Fibrillation: The LEDIOS Registry.

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) are effective in preventing thromboembolisms and reduce the risk of bleeding compared with warfarin. There are few reports on the outcomes of on-label reduced-dose NOACs. The aim of this study was to assess the safety and efficacy of on-label reduced-dose edoxaban in patients with atrial fibrillation (AF). METHODS: This study is a multi-center, prospective, non-interventional study to evaluate the safety and efficacy of on-label reduced-dose edoxaban in patients with AF. We evaluated outcomes of major bleeding, stroke or systemic embolism, all-cause death, and composite clinical outcomes. RESULTS: A total of 2,448 patients (mean age 75.0 ± 8.3 years, 801 [32.7%] males) was included in the present study. The mean CHA2DS2-VASc score was 3.7 ± 1.5. Major bleeding events occurred at a rate of 1.34%/yr. The event rate of strokes and systemic embolisms was 1.13%/yr. The overall net clinical outcomes occurred at a rate of 3.19%/yr. There were no significant differences according to the number of dose reduction criteria, renal dysfunction, or body weight. Higher HAS-BLED score and higher combination of CHA2DS2-VASc and HAS-BLED score was associated with an increased risk of composite clinical outcomes compared to the lower score groups. CONCLUSIONS: This study was the largest prospective real-world study to investigate the safety and efficacy of on-label low-dose edoxaban in an Asian population. Reduced-dose edoxaban can be used safely in patients with severe renal dysfunction or extremely low body weight. Our observation suggests that physicians should consider bleeding risk even in a low-dose regimen. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03554837.

Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death.

Intestinal epithelial cell (IEC) death is a common feature of inflammatory bowel disease (IBD) that triggers inflammation by compromising barrier integrity. In many patients with IBD, epithelial damage and inflammation are TNF-dependent. Elevated TNF production in IBD is accompanied by increased expression of the TNFAIP3 gene, which encodes A20, a negative feedback regulator of NF-κB. A20 in intestinal epithelium from patients with IBD coincided with the presence of cleaved caspase-3, and A20 transgenic (Tg) mice, in which A20 is expressed from an IEC-specific promoter, were highly susceptible to TNF-induced IEC death, intestinal damage, and shock. A20-expressing intestinal organoids were also susceptible to TNF-induced death, demonstrating that enhanced TNF-induced apoptosis was a cell-autonomous property of A20. This effect was dependent on Receptor Interacting Protein Kinase 1 (RIPK1) activity, and A20 was found to associate with the Ripoptosome complex, potentiating its ability to activate caspase-8. A20-potentiated RIPK1-dependent apoptosis did not require the A20 deubiquitinase (DUB) domain and zinc finger 4 (ZnF4), which mediate NF-κB inhibition in fibroblasts, but was strictly dependent on ZnF7 and A20 dimerization. We suggest that A20 dimers bind linear ubiquitin to stabilize the Ripoptosome and potentiate its apoptosis-inducing activity.

Effectiveness of the Early Staged Hybrid Approach for Treatment of Symptomatic Atrial Fibrillation: the Electrophysiology Study Could Be Deferred?

BACKGROUND: The efficacy of catheter ablation for persistent atrial fibrillation (AF) remains suboptimal. A hybrid approach of catheter ablation combined with totally thoracoscopic surgical ablation can improve outcomes. In this study, we evaluated the efficacy of the early staged hybrid procedure in hospital stay after totally thoracoscopic ablation compared to the stand-alone totally thoracoscopic ablation. METHODS: Patients who underwent totally thoracoscopic ablation from February 2012 to December 2018 were included in this study. We compared the outcomes of the totally thoracoscopic ablation only group versus the early staged hybrid procedure group. The primary outcome was recurrence of atrial tachyarrhythmia after three months of blanking period. The secondary outcome was repeated unplanned additional electrophysiology study and catheter ablation due to atrial tachyarrhythmia recurrence. RESULTS: A total of 306 patients (mean age, 56.8 ± 8.5 years; 278 [90.8%] males) was included in the study, with 81 patients in the early staged hybrid group and 225 patients in the stand-alone totally thoracoscopic ablation only group. The mean follow-up duration was 30.0 months. Overall arrhythmia-free survival showed no significant difference between the two groups (log-rank P = 0.402). There was no significant difference in the rate of repeat procedure between the two groups (log-rank = 0.11). CONCLUSION: The early staged hybrid procedure after thoracoscopic ablation could not improve the outcome of recurrence of atrial tachyarrhythmia. The second stage of electrophysiology study could be deferred to patients with recurrence of atrial tachyarrhythmia during follow up after totally thoracoscopic ablation.

IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease.

BACKGROUND & AIMS: Chronic alcohol consumption is a leading risk factor for the development of hepatocellular carcinoma (HCC), which is associated with a marked increase in hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA. METHODS: Genetic deletion and pharmacological blocking were used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC in mouse models and human specimens. RESULTS: We demonstrate that the global deletion of the Il-17ra gene suppressed HCC in alcohol-fed diethylnitrosamine-challenged Il-17ra-/- and major urinary protein-urokinase-type plasminogen activator/Il-17ra-/- mice compared with wild-type mice. When the cell-specific role of IL-17RA signaling was examined, the development of HCC was decreased in both alcohol-fed Il-17raΔMΦ and Il-17raΔHep mice devoid of IL-17RA in myeloid cells and hepatocytes, but not in Il-17raΔHSC mice (deficient in IL-17RA in hepatic stellate cells). Deletion of Il-17ra in myeloid cells ameliorated tumorigenesis via suppression of pro-tumorigenic/inflammatory and pro-fibrogenic responses in alcohol-fed Il-17raΔMΦ mice. Remarkably, despite a normal inflammatory response, alcohol-fed Il-17raΔHep mice developed the fewest tumors (compared with Il-17raΔMΦ mice), with reduced steatosis and fibrosis. Steatotic IL-17RA-deficient hepatocytes downregulated the expression of Cxcl1 and other chemokines, exhibited a striking defect in tumor necrosis factor (TNF)/TNF receptor 1-dependent caspase-2-SREBP1/2-DHCR7-mediated cholesterol synthesis, and upregulated the production of antioxidant vitamin D3. The pharmacological blocking of IL-17A/Th-17 cells using anti-IL-12/IL-23 antibodies suppressed the progression of HCC (by 70%) in alcohol-fed mice, indicating that targeting IL-17 signaling might provide novel strategies for the treatment of alcohol-induced HCC. CONCLUSIONS: Overall, IL-17A is a tumor-promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC. LAY SUMMARY: IL-17A is a tumor-promoting cytokine, which critically regulates inflammatory responses in macrophages (Kupffer cells and bone-marrow-derived monocytes) and cholesterol synthesis in steatotic hepatocytes in an experimental model of alcohol-induced HCC. Therefore, IL-17A may be a potential therapeutic target for patients with alcohol-induced HCC.

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress.

Pancreatic acinar cells possess very high protein synthetic rates as they need to produce and secrete large amounts of digestive enzymes. Acinar cell damage and dysfunction cause malnutrition and pancreatitis, and inflammation of the exocrine pancreas that promotes development of pancreatic ductal adenocarcinoma (PDAC), a deadly pancreatic neoplasm. The cellular and molecular mechanisms that maintain acinar cell function and whose dysregulation can lead to tissue damage and chronic pancreatitis are poorly understood. It was suggested that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis, but it is unknown whether impaired autophagy is a cause or a consequence of pancreatitis. To address this question, we generated Atg7(Δpan) mice that lack the essential autophagy-related protein 7 (ATG7) in pancreatic epithelial cells. Atg7(Δpan) mice exhibit severe acinar cell degeneration, leading to pancreatic inflammation and extensive fibrosis. Whereas ATG7 loss leads to the expected decrease in autophagic flux, it also results in endoplasmic reticulum (ER) stress, accumulation of dysfunctional mitochondria, oxidative stress, activation of AMPK, and a marked decrease in protein synthetic capacity that is accompanied by loss of rough ER. Atg7(Δpan) mice also exhibit spontaneous activation of regenerative mechanisms that initiate acinar-to-ductal metaplasia (ADM), a process that replaces damaged acinar cells with duct-like structures.

Restoration of Mitral Inflow Velocity Until Blanking Period Is Associated With Successful Ablation for Persistent Atrial Fibrillation.

Radiofrequency catheter ablation (RFCA) is a useful therapeutic option for atrial fibrillation (AF), although outcomes are less effective for persistent AF. The aim of this study was to elucidate the echocardiographic parameters associated with successful RFCA in patients with persistent AF.A total of 159 patients (mean age, 60.8 ± 9.6 years, 125 males [78.6%]) who underwent RFCA for persistent AF from April 2009 to May 2014 were included, retrospectively. Transthoracic echocardiography was performed at baseline, 3 months, 6 months, and 1 year following RFCA. The subjects were divided into 2 groups, a recurrence group and a non-recurrence group. One hundred eleven of the 159 patients (69.8%) remained free from recurrent atrial tachyarrhythmia during follow-up (mean, 20.6 ± 17.4 months). Peak A wave velocity (38.1 ± 14.1 in the recurrence group; 48.0 ± 20.7 in the non-recurrence group, P = 0.01), peak E wave velocity (76.4 ± 19.1 versus 68.8 ± 19.5, P = 0.03), deceleration time (196.3 ± 54.4 versus 219.9 ± 64.1, P = 0.04), and left atrial (LA) diameter (44.5 ± 7.3 versus 41.0 ± 5.6, P = 0.01) at 3 months after ablation were significantly different between the two groups. Among echocardiographic parameters, peak A wave velocity (OR 0.96, 95% confidence interval [CI] 0.92-0.99) and LA diameter (OR 1.13, 95% CI 1.011.25) were associated with AF recurrence.After RFCA for persistent AF, LA anatomical and functional changes occurred during a 3-month blanking period. Restoration of peak A wave velocity and LA size are associated with successful ablation.

Neurologic complications after allogeneic hematopoietic stem cell transplantation in children: analysis of prognostic factors.

Neurologic complications are serious complications after hematopoietic stem cell transplantation (HSCT) and significantly contribute to morbidity and mortality. The purpose of this study was to investigate the clinical features and prognosis in pediatric patients who had neurologic complications after allogeneic HSCT. We retrospectively reviewed the medical records of children and adolescents (19 years old or younger) who underwent allogeneic HSCT at our institution from 2000 to 2012. A total of 383 patients underwent 430 allogeneic transplantations. Among them, 73 episodes of neurologic complications occurred in 70 patients. The cumulative incidence of neurologic complications at day 400 was 20.0%. Almost two thirds of the episodes (63.0%, 46 of 73) occurred within 100 days after transplantation. Calcineurin inhibitor-related neurotoxicity was observed as the most common cause of neurotoxicity (47.9%, 35 of 73) and was significantly associated with earlier onset neurologic complications, seizure, and tremor. It also showed a significant association with lower probability of headache, abnormality of cranial nerve, and neurologic sequelae. In a multivariate analysis, days to neutrophil engraftment after HSCT, extensive chronic graft-versus-host disease (GVHD) and the existence of neurologic sequelae were identified as risk factors for mortality in patients who had neurologic complications (hazard ratio [HR], 1.08; 95% confidence interval [CI], 1.02 to 1.15; P = .011; HR, 5.98; 95% CI, 1.71 to 20.90; P = .005; and HR, 4.37; 95% CI, 1.12 to 17.05; P = .034, respectively). However, there was no significant difference in the 5-year overall survival between the patients who had neurologic complications without sequelae and the patients who did not have any neurologic complications (57.3% versus 61.8%, P = .906). In conclusion, we found that the major significant risk factors for mortality in pediatric recipients with neurologic complications were the existence of neurologic sequelae and extensive chronic GVHD.

Expression of herpes simplex virus 1 microRNAs in cell culture models of quiescent and latent infection.

To facilitate studies of herpes simplex virus 1 latency, cell culture models of quiescent or latent infection have been developed. Using deep sequencing, we analyzed the expression of viral microRNAs (miRNAs) in two models employing human fibroblasts and one using rat neurons. In all cases, the expression patterns differed from that in productively infected cells, with the rat neuron pattern most closely resembling that found in latently infected human or mouse ganglia in vivo.

Transient reversal of episome silencing precedes VP16-dependent transcription during reactivation of latent HSV-1 in neurons.

Herpes simplex virus type-1 (HSV-1) establishes latency in peripheral neurons, creating a permanent source of recurrent infections. The latent genome is assembled into chromatin and lytic cycle genes are silenced. Processes that orchestrate reentry into productive replication (reactivation) remain poorly understood. We have used latently infected cultures of primary superior cervical ganglion (SCG) sympathetic neurons to profile viral gene expression following a defined reactivation stimulus. Lytic genes are transcribed in two distinct phases, differing in their reliance on protein synthesis, viral DNA replication and the essential initiator protein VP16. The first phase does not require viral proteins and has the appearance of a transient, widespread de-repression of the previously silent lytic genes. This allows synthesis of viral regulatory proteins including VP16, which accumulate in the cytoplasm of the host neuron. During the second phase, VP16 and its cellular cofactor HCF-1, which is also predominantly cytoplasmic, concentrate in the nucleus where they assemble an activator complex on viral promoters. The transactivation function supplied by VP16 promotes increased viral lytic gene transcription leading to the onset of genome amplification and the production of infectious viral particles. Thus regulated localization of de novo synthesized VP16 is likely to be a critical determinant of HSV-1 reactivation in sympathetic neurons.

MASH as an emerging cause of hepatocellular carcinoma: current knowledge and future perspectives.

Hepatocellular carcinoma is one of the deadliest and fastest-growing cancers. Among HCC etiologies, metabolic dysfunction-associated fatty liver disease (MAFLD) has served as a major HCC driver due to its great potential for increasing cirrhosis. The obesogenic environment fosters a positive energy balance and results in a continuous rise of obesity and metabolic syndrome. However, it is difficult to understand how metabolic complications lead to the poor prognosis of liver diseases and which molecular mechanisms are underpinning MAFLD-driven HCC development. Thus, suitable preclinical models that recapitulate human etiologies are essentially required. Numerous preclinical models have been created but not many mimicked anthropometric measures and the course of disease progression shown in the patients. Here we review the literature on adipose tissues, liver-related HCC etiologies and recently discovered genetic mutation signatures found in MAFLD-driven HCC patients. We also critically review current rodent models suggested for MAFLD-driven HCC study.

Impact of Premature Ventricular Complex Burden on Ischemic Stroke in Patients with Non-Valvular Atrial Fibrillation.

Background/Objectives: Limited data are available regarding the prognostic impact of premature ventricular complex (PVC) burden in patients with atrial fibrillation (AF). We sought to compare clinical outcomes in patients with AF according to PVC burden via 24 h Holter monitoring. Methods: From January 2010 to December 2020, 4834 oral anticoagulant (OAC)-naïve non-valvular AF (NVAF) patients who underwent 24 h Holter monitoring were included for analysis. Results: Among the 4834 OAC-naïve NVAF patients, 2835 patients (58.6%) exhibited at least one PVC within a 24 h monitoring period, and 120 patients (2.5%) displayed a daily PVC burden exceeding 10%. In the follow-up echocardiography, patients with a daily PVC burden of ≥10% exhibited lower left ventricular ejection fraction, larger left atrial volume, and higher right ventricular systolic pressure and E/e' than those with a daily PVC burden of <10%. The risk of ischemic stroke (adjusted HR 2.332, p = 0.015) and heart failure admission (adjusted HR 2.147, p = 0.010) were significantly higher in the patients with a daily PVC burden of ≥10% than in those with a daily PVC burden of <10%. However, the incidence of cardiac death was not significantly different between the two groups. A daily PVC burden of ≥10% was independently associated with the risk of ischemic stroke in the OAC-naïve NVAF patients, irrespective of the CHA2DS2-VASc score, AF type, and left atrial size. Conclusions: The current results suggest that evaluating and monitoring the burden of PVCs in patients with NVAF is an important aspect of predicting stroke and heart failure admission.