The World Health Organization recognizes digital health as a key driver for sustainable health systems. Digital health is broad concept that refers to the use of digital technologies to improve health and healthcare. Mobile health is part of digital health and refers to the use of mobile devices such as smartphones, tablets, and wearable gadgets to deliver health-related services. By proactively utilizing personal health records from mHealth, in conjunction with electronic health records, advanced medical practices can be achieved. This integration facilitates app-based patient education and encouragement, lifestyle modification, and efficient sharing of medical information between hospitals. Beyond emergency care, information sharing enables patients to visit multiple healthcare facilities without redundant tests or unnecessary referrals, reducing the burden on both patients and healthcare providers.

Background: In patients with atrial fibrillation-related ischemic stroke despite oral anticoagulation (AFIDA), left atrial appendage closure (LAAC) may be an additional strategy to prevent further stroke events.

Methods and Results: AFIDA was defined as ischemic stroke occurring despite ≥3 weeks of oral anticoagulation (OAC). We evaluated patients with AFIDA treated either with OAC alone (n=141; further divided into aggressive OAC [n=73] and conventional OAC [n=68] subgroups) or with additional LAAC (+LAAC; n=95; further divided into continued OAC [n=44] and discontinued OAC within 1 year after LAAC [n=51] subgroups). Patients in the +LAAC group were younger, had higher HAS-BLED scores, and lower HELT-E₂S₂scores. Three-year cumulative incidence rates of ischemic stroke and major bleeding were comparable between the OAC alone and +LAAC groups (15.2% vs. 14.5% [log-rank P=0.75] and 23.4% vs. 5.3% [log-rank P=0.38], respectively), whereas those of fatal or disabling stroke and fatal bleeding were lower in the +LAAC than OAC alone group (3.4% vs. 14.7% [log-rank P=0.06] and 0% vs. 6.0% [log-rank P=0.03], respectively). Results of propensity score-matched and subgroup analyses were largely consistent with those of the main analysis. Notably, fatal bleeding occurred only in patients switched to aggressive OAC.

Conclusions: LAAC may potentially prevent fatal or disabling stroke and fatal bleeding in patients with AFIDA. These hypothesis-generating findings support the need for randomized controlled trials.

Background: The impact of postoperative atrial fibrillation (POAF) after coronary artery bypass grafting (CABG) on long-term clinical outcomes remains controversial.

Methods and Results: Of 14,927 consecutive patients with their first coronary revascularization in the CREDO-Kyoto Registry Cohort-3, we extracted data for 1,483 undergoing CABG without prior atrial fibrillation (AF). POAF was defined as newly documented AF during hospitalization for CABG and was diagnosed in 337 (23%) patients during the index hospitalization. The remaining 1,146 patients were categorized as the non-POAF group. The median follow-up after discharge was 5.7 years. The cumulative 5-year incidence of all-cause death did not differ significantly between the POAF and non-POAF groups (15.9% vs. 13.0%, respectively; P=0.38), whereas the cumulative 5-year incidence of stroke, heart failure, and Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding was significantly higher in the POAF group. There was no excess adjusted risk of the POAF group relative to the non-POAF group for all-cause death (hazard ratio 0.96; 95% confidence interval 0.70–1.31; P=0.81). The risk of the POAF group relative to the non-POAF group was numerically higher for stroke and heart failure, and significantly higher for BARC type 3 or 5 bleeding.

Conclusions: The long-term risk of patients with POAF relative to those without was significantly higher for major bleeding and numerically higher for stroke and heart failure, with no difference for mortality.

Background: Metabolic derangements are associated with incident and recurrent atrial fibrillation (AF), in addition to the development of metabolic dysfunction-associated fatty liver disease (MAFLD). A recent study reported MAFLD was associated with significantly increased arrhythmia recurrence rates following AF ablation in Western patients. However, in Asian patients with a higher prevalence of non-obese MAFLD, it is not clear whether MAFLD affects recurrence after AF ablation regardless of obesity. This study investigated the impact of MAFLD on AF recurrence in Japanese patients.

Methods and Results: We enrolled 872 patients who underwent AF ablation and assessed the relationship between MAFLD and AF recurrence. The prevalence of MAFLD was significantly higher in the group with than without AF recurrence. Although the liver/spleen ratio was significantly lower among patients with than without AF recurrence, the liver fibrosis score did not differ significantly between the 2 groups. Multivariate Cox proportional hazards regression analysis identified MAFLD, but not body mass index, as a factor independently associated with AF recurrence (adjusted hazard ratio 2.62; 95% confidence interval 1.44–4.80; P=0.002). We found a significant interaction between MAFLD and homeostasis model assessment of insulin resistance (HOMA-IR; P for interaction=0.034).

Conclusions: MAFLD is an independent risk factor for recurrence after AF ablation in Japanese patients regardless of obesity, and its effects are likely heterogeneous, with a greater impact in the presence of insulin resistance.

Background: Atrial fibrillation (AF) recurrence after ablation requires predictors for better management. This study evaluated early post-ablation changes in echocardiographic parameters, clarifying the relative importance of left ventricle (LV) diastolic function and left atrium (LA) strain for recurrence prediction.

Methods and Results: The study prospectively enrolled 165 consecutive patients undergoing de novo AF ablation between 2019 and 2021. Echocardiography was performed before and 3 months after ablation. Three months after ablation, LA volume and LA strain (reservoir and contraction phases) decreased significantly and the LV ejection fraction improved. Extrapulmonary vein LA ablation was associated with significantly lower LA strain at 3 months. Over a median follow-up of 359 days, atrial tachyarrhythmia recurred in 45 (27.3%) patients. Three months after ablation, there was no significant difference in LA strain between groups with and without recurrence, but mitral E/e′ and right ventricular systolic pressure (RVSP) were significantly higher in the group with recurrence (mitral E/e′ 7.4±2.2 vs. 10.4±4.1; RVSP 23.1±3.5 vs. 28.4±4.8 mmHg; P<0.001 for both). Multivariable analysis identified E/e′ and RVSP at 3 months as independent predictors of recurrence (hazard ratios 1.246 and 1.111, respectively), but not LA strain.

Conclusions: Following AF ablation, hemodynamic factors appear to be more significant predictors of recurrence than LA strain. Assessment of LV diastolic function during the early post-ablation period may help identify patients at high risk of recurrence.

Background: Brugada syndrome (BrS) is an arrhythmic disease associated with SCN5A loss-of-function variants. We identified a novel single nucleotide substitution, SCN5A c.1338G>A, in the last codon of exon10 in a patient with drug-induced BrS. The aim of this study was to investigate the impact of this splice-altering variant and examine whether antisense oligonucleotides (ASOs) could correct the splice alteration.

Methods and Results: Genomic DNA was extracted from the patient’s blood lymphocytes. Coding exons of inherited arrhythmia genes were screened and SCN5A c.1338G>A was identified. SpliceAI predicted its prominent potential to alter splicing among 168 single nucleotide variants in the SCN5A region including 10 variants with allele frequency (AF) <0.01, and the usage of a cryptic splice donor site 4 bp downstream from the authentic splice donor site. Minigene splicing reporter assays were performed using HEK-293 cells and induced pluripotent stem cells–cardiomyocytes, and successfully demonstrated a dominant selection of the predicted splice site. Three different ASOs were tested in the same platform. Although the ASOs reduced the production of splice error products, they did not succeed in increasing authentically spliced products.

Conclusions: We confirmed a splice site alteration by SCN5A c.1338G>A and propose extended use of SpliceAI for screening a target genomic region. The attempts to correct mis-splicing near the canonical splice site were not entirely successful, so further development of technology is awaited.

Background: Loss-of-function SCN5A variants are primarily associated with Brugada syndrome (BrS), but can also present with overlapping phenotypes. We investigated Cys1384Phe of SCN5A, a novel missense variant associated with BrS, sick sinus syndrome (SSS), and dilated cardiomyopathy (DCM).

Methods and Results: This study included a large 4-generation Japanese family consisting of 15 individuals (1 proband and 14 family members). Among them, the proband, a cousin, a second cousin and the second cousin’s father were diagnosed with BrS. Two of these 4 BrS patients experienced VF events, while the other 2 remained asymptomatic. Another cousin was diagnosed with DCM, and 3 additional family members exhibited complete right bundle branch block and/or SSS. Comprehensive genetic analysis using a target panel sequencing identified a novel missense variant, Cys1384Phe in SCN5A, in the proband and affected family members; however, the phenotypes were different. Whole-cell patch-clamp experiments using HEK293 cells transfected wild-type or Cys1384Phe plasmid demonstrated a complete loss-of-function in the sodium current of the Cys1384Phe cells. Furthermore, the heterozygous expression of Cys1384Phe and wild-type (WT) channels showed a significant reduction of peak sodium current compared with the WT, suggesting a dominant-negative suppression, but no trafficking defect was observed.

Conclusions: The novel Cys1384Phe variant in SCN5A is a complete loss-of-function mutation with dominant-negative suppression, and associated with overlapping phenotypes of BrS, SSS, and DCM.

Background: Despite active research into the pathophysiology of Brugada syndrome (BrS), the mechanisms of the genesis of changes in the characteristic electrocardiogram (ECG) are still controversial.

Methods and Results: Using multiscale computer simulation of ECGs, we compared 3 hypotheses to identify the mechanisms of the BrS-type ECG caused by a mutation in cardiac sodium channels. In addition to the dominant repolarization disorder and depolarization disorder hypotheses, we tested a new hypothesis assuming the combination of a slow conduction property, upregulation of transient outward potassium current channels, and reduced expression levels of sodium channels in the right ventricular outflow tract (embryonic phenotype model). We found that only the embryonic phenotype model reproduced the clinically observed BrS-type ECG by strongly inhibiting sodium current selectively in the right ventricular outflow tract. We also simulated a ventricular wedge experiment and confirmed that strong inhibition of the sodium current was the prerequisite for a change in the ECG.

Conclusions: Strong selective inhibition of the sodium current in the right ventricular outflow tract generates the characteristic BrS-type ECG in the precordial leads without affecting the waveforms in other lead positions. This change can only be achieved using the embryonic phenotype model in which reduced expression levels of sodium channels play an essential role.

Background: The usefulness of non-sustained ventricular tachycardia (NSVT) in predicting sudden cardiac death is not clear. The Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan (HINODE) investigated the effectiveness of implantable cardioverter defibrillator (ICD) treatment for primary prevention in Japanese patients. This subanalysis examined associations between NSVT and clinical outcomes.

Methods and Results: Patients with ICD/cardiac resynchronization therapy defibrillator (CRT-D) for primary prevention (n=164) were divided into NSVT (n=25) and no NSVT (n=139) groups. NSVT was defined as ventricular tachycardia of <30 s duration regardless of pulse rate. The median follow-up period was 19 months, mean patient age was 67 years, and 21% of patients were female. There were no significant differences between the 2 groups in the frequency ischemic cardiomyopathy, mean left ventricular ejection fraction, or (in Kaplan-Meier analysis) in all-cause mortality (log-rank P=0.613), ventricular arrhythmia (VA; log-rank P=0.282), or the composite endpoint of all-cause death and VA events (log-rank P=0.352). Cox proportional hazards analysis indicated that NSVT was not a prognostic factor.

Conclusions: Prognosis was similar between the NSVT and no NSVT groups. NSVT, although recommended in guidelines for risk stratification, was not associated with appropriate ICD therapy in patients with ICD/CRT-D for primary prevention. The utility of NSVT in guiding ICD indication may depend on its definition and the characteristics of the studied population, and requires further investigation.

Background: Cardiac sarcoidosis (CS) is a rare, potentially life-threatening condition associated with ventricular tachycardia (VT). Outcomes of catheter ablation for VT in patients with histologically diagnosed sarcoidosis and those with suspected or clinically diagnosed sarcoidosis have not been well studied. This study addressed this knowledge gap.

Methods and Results: We conducted an observational retrospective chart review of patients with CS who underwent VT ablation between 2007 and 2024 at Mayo Clinic Hospital. The cohort was divided into 2 groups: those with histologically diagnosed sarcoidosis and those with clinical or suspected sarcoidosis diagnosed according to Japanese Circulation Society 2016 guidelines. The primary endpoints were VT recurrence, cardiovascular mortality, and heart transplantation. Eighty-eight patients were included in the study: 33 with histologically confirmed CS and 55 with clinical/suspected CS. Systemic sarcoidosis was more common in the group with histologically confirmed CS, whereas mid-myocardial non-ischemic late gadolinium enhancement was more prevalent in the group with clinical/suspected CS. The 1-year composite event-free survival rate was 56.1%. In multivariate analysis, systemic sarcoidosis was independently associated with lower event-free survival rates.

Conclusions: Patients with histologically confirmed CS had worse VT ablation outcomes than those with clinical/suspected CS. This difference may be driven by a higher prevalence of systemic sarcoidosis in the former group. These findings highlight the need for a comprehensive management approach in both groups.

Background: The Amplatzer^TMPFO Occluder was approved for marketing in Japan in May 2019, and the Amplatzer PFO Occluder Japan Post-Marketing Surveillance (PFO Japan PMS) study started in December 2019. This analysis presents clinical outcomes of study patients through 1 year of follow-up.

Methods and Results: PFO Japan PMS is a prospective single-arm multicenter clinical study. Eligible patients were indicated for patent foramen ovale (PFO) closure and underwent an implant attempt with the Amplatzer^TMPFO Occluder, with no age restrictions. PFO closure was evaluated at 1 year via a bubble study, and patients will be followed for 3 years. From December 2019 to July 2021, 500 patients were enrolled across 53 sites. The mean (±SD) patient age was 52.7±15.4 years, with 29.8% of patients aged >60 years. Low adverse event rates were observed through 1 year of follow-up, including atrial fibrillation (2.4%; predominantly transient and within the first 30 days) and ischemic stroke (0.6%). Among patients in whom a 1-year bubble study was performed, a high rate (91.5%) of clinically relevant PFO closure (<20 bubbles) was achieved.

Conclusions: Through 1 year of follow-up in this real-world Japanese study with 30% of patients aged >60 years, a high degree of closure was achieved with the Amplatzer^TMPFO Occluder, along with low rates of atrial fibrillation, ischemic stroke, and overall adverse events.

Background: In Japan, the implantation of implantable cardioverter defibrillators (ICD) for the primary prevention of sudden cardiac death (SCD) is not covered by insurance reimbursement, and the underuse of ICDs has been noted. Therefore, this study analyzed the medical costs incurred due to a lack of primary prevention ICD therapy for SCD.

Methods and Results: This retrospective cohort study analyzed data from 4 advanced critical care centers between January 2020 and December 2024. From a database of 3,606 cases of cardiac arrest, there were 348 patients with a documented rhythm at the time of arrest that could have been treated with an ICD. Of these patients, 43 (12.4%) had documented evidence of heart failure treatment and were eligible for ICD implantation before experiencing a cardiac arrest. The total mean (±SD) medical cost for these patients was US $11,679±14,666 (¥1,775,150±2,229,272).

Conclusions: In this multicenter retrospective analysis, we identified a subset of patients who were eligible for primary prevention ICD therapy but did not receive it prior to experiencing sudden cardiac arrest. These cases were associated with substantial post-arrest medical costs. Our findings highlight the potential clinical and economic impact of the underutilization of ICDs in Japan and suggest that broader implementation of guideline-directed ICD therapy for primary prevention may reduce both mortality and healthcare expenditure.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease with a poor prognosis and no curative therapy. It may present as arrhythmogenic sudden cardiac death and inevitably progress to terminal heart failure due to the loss of contractile tissue. This study aimed to generate knock-in (KI) mice carrying the 2 genetic variants (DSG2 p.R292C and p.D494A) most frequently found in Japanese ARVC patients, characterize their cardiac phenotype, and compare the results with those of human ARVC.

Methods and Results: Variants were introduced using CRISPR/Cas9 genome editing at the corresponding mouse locations: Dsg2 p.R297C (RC) and p.D499A (DA). Cardiac function, morphology, and electrophysiology were evaluated using echography, magnetic resonance imaging, and telemetry. Tissue and cardiomyocytes were examined histologically. All mice with the variants developed biventricular cardiac dysfunction after 8 weeks of age, and it progressed with age. There was a significant variability in phenotype expression. Mice with RC died suddenly at 9 weeks of age. Some homozygous RC mice showed arrhythmia and conduction abnormalities on telemetry. In both variants, staining of cardiac sections revealed significant fibrosis, and apoptosis was detected using the terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling assay.

Conclusions: We generated a KI ARVC mouse model with significant similarities to human disease. This model could be used for the elucidation of pathogenesis and the development of optimal therapy for ARVC.