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.

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.

Optimal Dose of Edoxaban for Very Elderly Atrial Fibrillation Patients at High Risk of Bleeding: The LEDIOS Registry.

BACKGROUND AND OBJECTIVES: Optimal anticoagulation in very elderly patients is challenging due to the high risk of anticoagulant-induced bleeding. The aim of this study was to assess outcomes of on-label reduced-dose edoxaban (30 mg) in very elderly patients who had additional risk factors for bleeding. METHODS: This was a multi-center, prospective, non-interventional observational study to evaluate the efficacy and safety of on-label reduced-dose edoxaban in atrial fibrillation (AF) patients 80 years of age or older and who had more than 1 risk factor for bleeding. RESULTS: A total of 2448 patients (mean age 75.0±8.3 years, 801 [32.7%] males) was included in the present study, and 586 (23.9%) were 80 years of age or older with additional risk factors for bleeding. Major bleeding events occurred frequently among very elderly AF patients who had additional bleeding risk factors compared to other patients (unadjusted hazard ratio [HR], 2.16; 95% confidence interval [CI], 1.16-4.02); however, there were no significant differences in stroke incidence (HR, 1.86; 95% CI, 0.98-3.55). There were no significant differences for either factor after adjusting for age and sex (adjusted HR, 1.65; 95% CI, 0.75-3.62 for major bleeding; adjusted HR, 1.13; 95% CI, 0.51-2.50 for stroke). CONCLUSIONS: In very elderly AF patients with comorbidities associated with greater risk of bleeding, the incidence of major bleeding events was significantly increased. In addition, risk of stroke showed tendency to increase in same population. Effective anticoagulation therapy might be important in these high-risk population, and close observation of bleeding events might also be required. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03554837.

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.

Artificial intelligence predicts undiagnosed atrial fibrillation in patients with embolic stroke of undetermined source using sinus rhythm electrocardiograms.

BACKGROUND: Artificial intelligence (AI)-enabled sinus rhythm (SR) electrocardiogram (ECG) interpretation can aid in identifying undiagnosed paroxysmal atrial fibrillation (AF) in patients with embolic stroke of undetermined source (ESUS). OBJECTIVE: The purpose of this study was to assess the efficacy of an AI model in identifying AF based on SR ECGs in patients with ESUS. METHODS: A transformer-based vision AI model was developed using 737,815 SR ECGs from patients with and without AF to detect current paroxysmal AF or predict the future development of AF within a 2-year period. Probability of AF was calculated from baseline SR ECGs using this algorithm. Its diagnostic performance was further tested in a cohort of 352 ESUS patients from 4 tertiary hospitals, all of whom were monitored using an insertable cardiac monitor (ICM) for AF surveillance. RESULTS: Over 25.1-month follow-up, AF episodes lasting ≥1 hour were identified in 58 patients (14.4%) using ICMs. In the receiver operating curve (ROC) analysis, the area under the curve for the AI algorithm to identify AF ≥1 hour was 0.806, which improved to 0.880 after integrating the clinical parameters into the model. The AI algorithm exhibited greater accuracy in identifying longer AF episodes (ROC for AF ≥12 hours: 0.837, for AF ≥24 hours: 0.879) and a temporal trend indicating that the AI-based AF risk score increased as the ECG recording approached the AF onset (P for trend <.0001). CONCLUSIONS: Our AI model demonstrated excellent diagnostic performance in predicting AF in patients with ESUS, potentially enhancing patient prognosis through timely intervention and secondary prevention of ischemic stroke in ESUS cohorts.

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.

Clinical impact of capsulectomy during cardiac implantable electronic device generator replacement: a prospective randomized trial.

BACKGROUND: The avascular capsule around the generator of the cardiac implantable electronic device (CIED) could be susceptible to bacterial colonization and source of infection. Capsulectomy during CIED generator replacement may be beneficial in preventing device infection, but there is a lack of evidence. METHODS: This prospective randomized trial, conducted from December 2013 to December 2019, included 195 patients divided equally into two groups. In the intervention group (n = 97), capsule removal was performed on the floor of the pocket, while it was not performed in the control group (n = 98). In both groups, swab culture was performed in the pocket. The primary outcome was the occurrence of device infection requiring pocket revision. RESULTS: A total of 195 patients were included (mean age 70.2 ± 13.6 years, 55.4% women), with an average follow-up period of 54.3 ± 28.9 months. Among 182 patients undergoing microbiological cultures of pockets, 19 (10.4%) were confirmed positive, and Staphylococcus species were identified most frequently. The primary outcome occurred in 4 (2.1%), and there was no significant difference between the two groups (3.1% vs. 1.0%, p = 0.606). Hematoma has occurred in 10 patients (3.1% vs. 7.1%, p = 0.338), one of them required wound revision. In multivariable analysis, the occurrence of hematoma was the only independent risk factor associated with device infection (HR 13.6, 95% CI 1.02-181.15, p = 0.048). CONCLUSIONS: In this long-term prospective study, capsulectomy during the replacement of the generator did not reduce the incidence of device infection. There was no association between bacterial colonization in the capsule around the generator and CIED infection.

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.

Exercise capacity and risk of incident atrial fibrillation in healthy adults.

BACKGROUND/AIMS: Atrial fibrillation (AF) is a common arrhythmia and is associated with cardiovascular morbidity and mortality. It is important to identify and control the modifiable risk factors of AF. We aimed to examine the association of exercise capacity with the risk of incident AF within 3 years in healthy subjects. METHODS: We evaluated asymptomatic adults who had undergone more than two consecutive health checkups. We included subjects who exhibited normal sinus rhythm on the first health examination and who developed AF on the second or subsequent health examinations. Subjects who underwent cardiopulmonary exercise testing within 3 years before the diagnosis of AF were examined. RESULTS: The study population in the analyses included 428 cases (mean age 58.4 ± 7.6 yr, male 95.6%). There were significant differences in maximal systolic blood pressure (SBP; case 169.4 ± 24.2 vs. control 173.9 ± 22.3 mmHg), peak VO2 (29.5 ± 5.4 vs. 30.4 ± 4.8 mL/kg per minute), and maximal metabolic equivalents (METs; 8.5 ± 1.6 vs. 8.7 ± 1.4) between the two groups. In the multivariable logistic models, adjusted odds ratios were 0.99 for maximal SBP (95% confidence interval [CI] 0.98-0.99), 0.97 for peak VO2 (95% CI 0.95-0.99), and 0.91 for maximal METs (95% CI 0.83-0.98). CONCLUSION: We demonstrated that poorer exercise capacity was associated with the development of AF in a healthy population. A prospective, systematic trial is necessary to confirm that appropriate exercise training will be beneficial in preventing the development of AF in such patients.

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.

Non-Invasive Risk Assessment and Prediction of Mortality in Patients Undergoing Coronary Artery Bypass Graft Surgery.

Objectives: Heart rate turbulence (HRT) and T-wave alternans (TWA), non-invasive markers of cardiac autonomic dysfunction, and ventricular repolarization abnormality, reportedly, predict the risk of cardiovascular death after myocardial infarction. We investigated whether pre-operative assessment of HRT and/or TWA could predict long-term mortality following coronary artery bypass graft (CABG) surgery. Methods: From May 2010 to December 2017, patients undergoing elective CABG and receiving 24 h ambulatory electrocardiogram monitoring 1 to 5 days prior to CABG surgery were prospectively enrolled. Pre-operative HRT and TWA were measured using a 24 h ambulatory electrocardiogram. The relative risk of cardiac or overall death was assessed according to abnormalities of HRT, TWA, or left ventricular ejection fraction (LV EF). Results: During the mean follow-up period of 4.6 ± 3.9 years, 40 adjudicated overall (5.9%/yr) and 5 cardiac deaths (0.9%/yr) occurred in 146 enrolled patients (64.9 ± 9.3 years; 108 males). Patients with abnormal HRT exhibited significantly higher relative risks of cardiac death (adjusted hazard ratio [HR] 24.9, 95% confidence interval [CI] 1.46-427) and all-cause death (adjusted HR 5.77, 95% CI 2.34-14.2) compared to those with normal HRT. Moreover, abnormal HRT plus abnormal TWA and LV EF < 50% was associated with a greater elevation in cardiac and overall mortality risk. The predictive role of abnormal HRT with/without abnormal TWA for all-cause death was likely more prominent in patients with mildly reduced (35 to 50%) or preserved (≥50%) LV EF. Abnormal HRT plus abnormal TWA and LV EF < 50% showed high negative predictive value in cardiac and overall mortality risk. Conclusions: Assessment of pre-operative HRT and/or TWA predicted mortality risk in patients undergoing elective CABG. Combined analysis of HRT, TWA, and LVEF enhanced the prognostic power. In particular, the predictive value of HRT was enhanced in patients with preserved or mid-range LV EF.

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.

Association of reproductive factors with cardiovascular disease risk in pre-menopausal women: nationwide population-based cohort study.

BACKGROUND: Although the morbidity and mortality of cardiovascular diseases (CVD) are rising in young women, the risk factors of CVD among Korean pre-menopausal women have not been intensively investigated. AIMS: To determine how age at menarche and other female reproductive factors are associated with the risk of CVD in pre-menopausal women. METHODS AND RESULTS: A total of 1 088 992 pre-menopausal women who participated in health screening in 2009 were included. The study outcomes were myocardial infarction (MI) and ischaemic stroke. Cox proportional hazards regression analysis was conducted with adjustment of traditional CVD risk factors and reproductive factors. RESULTS: Mean age was 43.8 ± 5.3 years (98.9%, < 55 years), 3.5% were current smokers, and 1.2% were heavy drinkers. During a mean follow-up of 8.3years [9 032 685.9 person-years (PY)], there were 10 876 CVD events (1.0 per 1000 PY).With later menarche, the risk of CVD increased; ≤12 years [adjusted hazard ratio (HR) 1.04, 95% confidence interval 0.93-1.16], 13 years (reference), 14 years (1.06, 0.98-1.14), 15 years (1.15, 1.07-1.24), 16 years (1.23, 1.14-1.34), and ≥17 years (1.33, 1.24-1.44). Compared with non-users, oral contraceptives (OC) users (≥1 year) had an increased risk of CVD (1.11, 1.01-1.22) (P for trend = 0.007). CONCLUSIONS: Later menarche than the mean age at menarche (13 years old) and the use of OC (≥1 year) were associated with a higher risk of CVD, after adjusting for traditional cardiovascular risk factors. This study suggests that female reproductive factors could be unique risk factors for CVD in pre-menopausal women.

Association of typical atrial flutter and cavotricuspid isthmus ablation on clinical recurrence after cryoballoon ablation for atrial fibrillation.

Typical atrial flutter commonly occurs in patients with atrial fibrillation (AF). Limited information exists regarding the effects of concurrent atrial flutter on the long-term outcomes of rhythm control. This study investigated the association between concurrent typical atrial flutter and cavotricuspid isthmus (CTI) ablation and the recurrence of atrial arrhythmia. The data were obtained from a multicenter registry of cryoballoon ablation for AF (n = 2,689). Patients who were screened for typical atrial flutter were included in the analysis (n = 1,907). All the patients with typical atrial flutter underwent CTI ablation. The primary endpoint was the late recurrence of atrial arrhythmia, including AF, atrial flutter, and atrial tachycardia. Among the 1,907 patients, typical atrial flutter was detected in 493 patients (25.9%). Patients with concurrent atrial flutter had a lower incidence of persistent AF and a smaller size of the left atrium. Patients with atrial flutter had a significantly lower recurrence rate of atrial arrhythmia (19.7% vs. 29.9%, p < 0.001). In patients with atrial flutter, the recurrence rate of atrial tachycardia or atrial flutter was more frequent (7.3% vs. 4.7%, p = 0.028), but the recurrence rate of AF was significantly lower (17.0% vs. 29.4%, p < 0.001). Atrial flutter has been identified as an independent predictor of the primary endpoint (adjusted hazard ratio, 0.704; 95% confidence interval, 0.548-0.906; p = 0.006). Typical atrial flutter in patients with AF may serve as a positive marker of the recurrence of atrial arrhythmia, and performing CTI ablation in this population is associated with a reduced likelihood of AF recurrence. Performing routine screening and ablation procedures for coexisting atrial flutter may improve the clinical outcomes of AF.

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.

Genuine selective caspase-2 inhibition with new irreversible small peptidomimetics.

Caspase-2 (Casp2) is a promising therapeutic target in several human diseases, including nonalcoholic steatohepatitis (NASH) and Alzheimer's disease (AD). However, the design of an active-site-directed inhibitor selective to individual caspase family members is challenging because caspases have extremely similar active sites. Here we present new peptidomimetics derived from the VDVAD pentapeptide structure, harboring non-natural modifications at the P2 position and an irreversible warhead. Enzyme kinetics show that these new compounds, such as LJ2 or its specific isomers LJ2a, and LJ3a, strongly and irreversibly inhibit Casp2 with genuine selectivity. In agreement with the established role of Casp2 in cellular stress responses, LJ2 inhibits cell death induced by microtubule destabilization or hydroxamic acid-based deacetylase inhibition. The most potent peptidomimetic, LJ2a, inhibits human Casp2 with a remarkably high inactivation rate (k3/Ki ~5,500,000 M-1 s-1), and the most selective inhibitor, LJ3a, has close to a 1000 times higher inactivation rate on Casp2 as compared to Casp3. Structural analysis of LJ3a shows that the spatial configuration of Cα at the P2 position determines inhibitor efficacy. In transfected human cell lines overexpressing site-1 protease (S1P), sterol regulatory element-binding protein 2 (SREBP2) and Casp2, LJ2a and LJ3a fully inhibit Casp2-mediated S1P cleavage and thus SREBP2 activation, suggesting a potential to prevent NASH development. Furthermore, in primary hippocampal neurons treated with ß-amyloid oligomers, submicromolar concentrations of LJ2a and of LJ3a prevent synapse loss, indicating a potential for further investigations in AD treatment.

Clinical Outcomes of Rhythm Control Strategies for Asymptomatic Atrial Fibrillation According to the Quality-of-Life Score: The CODE-AF (Comparison Study of Drugs for Symptom Control and Complication Prevention of Atrial Fibrillation) Registry.

Background Atrial fibrillation (AF) is associated with an increased risk of poor cardiovascular outcomes; appropriate rhythm control can reduce the incidence of these adverse events. Therefore, catheter ablation is recommended in symptomatic patients with AF. The aims of this study were to compare AF-related outcomes according to a baseline symptom scale score and to determine the best treatment strategy for asymptomatic patients with AF. Methods and Results This study enrolled all patients who completed a baseline Atrial Fibrillation Effect on Quality-of-Life (AFEQT) survey in a prospective observational registry. The patients were divided into 2 groups according to AFEQT score at baseline; scores ≤80 were defined as symptomatic, whereas scores >80 represented asymptomatic patients. The primary outcome was defined as a composite of hospitalization for heart failure, ischemic stroke, or cardiac death. This study included 1515 patients (mean age: 65.7±10.5 years; 998 [65.9%] men). The survival curve showed a poorer outcome in the symptomatic group compared with the asymptomatic group (log-rank P=0.04). Rhythm control led to a significantly lower risk of a composite outcome in asymptomatic patients (hazard ratio [HR], 0.47 [95% CI, 0.27-0.84], P=0.01). Rhythm control was associated with more favorable composite outcomes in the asymptomatic group with paroxysmal AF, left atrium diameter ≤50 mm, and CHA2DS2-VASc score ≥3. Conclusions Symptomatic patients with AF experienced more adverse outcomes compared with asymptomatic patients. In asymptomatic patients with AF, a strategy of rhythm control improved the outcomes, especially with paroxysmal AF, smaller left atrium size, or higher stroke risk. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02786095.

PIDDosome-SCAP crosstalk controls high-fructose-diet-dependent transition from simple steatosis to steatohepatitis.

Sterol deficiency triggers SCAP-mediated SREBP activation, whereas hypernutrition together with ER stress activates SREBP1/2 via caspase-2. Whether these pathways interact and how they are selectively activated by different dietary cues are unknown. Here, we reveal regulatory crosstalk between the two pathways that controls the transition from hepatosteatosis to steatohepatitis. Hepatic ER stress elicited by NASH-inducing diets activates IRE1 and induces expression of the PIDDosome subunits caspase-2, RAIDD, and PIDD1, along with INSIG2, an inhibitor of SCAP-dependent SREBP activation. PIDDosome assembly activates caspase-2 and sustains IRE1 activation. PIDDosome ablation or IRE1 inhibition blunt steatohepatitis and diminish INSIG2 expression. Conversely, while inhibiting simple steatosis, SCAP ablation amplifies IRE1 and PIDDosome activation and liver damage in NASH-diet-fed animals, effects linked to ER disruption and preventable by IRE1 inhibition. Thus, the PIDDosome and SCAP pathways antagonistically modulate nutrient-induced hepatic ER stress to control non-linear transition from simple steatosis to hepatitis, a key step in NASH pathogenesis.

An Artificial Intelligence Algorithm With 24-h Holter Monitoring for the Identification of Occult Atrial Fibrillation During Sinus Rhythm.

Background: Subclinical atrial fibrillation (AF) is one of the pathogeneses of embolic stroke. Detection of occult AF and providing proper anticoagulant treatment is an important way to prevent stroke recurrence. The purpose of this study was to determine whether an artificial intelligence (AI) model can assess occult AF using 24-h Holter monitoring during normal sinus rhythm. Methods: This study is a retrospective cohort study that included those who underwent Holter monitoring. The primary outcome was identifying patients with AF analyzed with an AI model using 24-h Holter monitoring without AF documentation. We trained the AI using a Holter monitor, including supraventricular ectopy (SVE) events (setting 1) and excluding SVE events (setting 2). Additionally, we performed comparisons using the SVE burden recorded in Holter annotation data. Results: The area under the receiver operating characteristics curve (AUROC) of setting 1 was 0.85 (0.83-0.87) and that of setting 2 was 0.84 (0.82-0.86). The AUROC of the SVE burden with Holter annotation data was 0.73. According to the diurnal period, the AUROCs for daytime were 0.83 (0.78-0.88) for setting 1 and 0.83 (0.78-0.88) for setting 2, respectively, while those for nighttime were 0.85 (0.82-0.88) for setting 1 and 0.85 (0.80-0.90) for setting 2. Conclusion: We have demonstrated that an AI can identify occult paroxysmal AF using 24-h continuous ambulatory Holter monitoring during sinus rhythm. The performance of our AI model outperformed the use of SVE burden in the Holter exam to identify paroxysmal AF. According to the diurnal period, nighttime recordings showed more favorable performance compared to daytime recordings.

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.