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: Changes in mitral valve (MV) morphology during MV transcatheter edge-to-edge repair (MV-TEER) are associated with short-term reduction of mitral regurgitation (MR). However, whether these changes are associated with prognosis remains unclear. Using 3-dimensional transesophageal echocardiography, this study evaluated the impact of MV morphological parameters on the mid-term prognosis of patients with functional MR (FMR).

Methods and Results: We analyzed 99 patients with FMR who were treated with MV-TEER. The primary endpoint was a composite of all-cause mortality and hospitalization due to heart failure. Patients were divided into 2 groups based on the post-procedural sphericity index of the mitral valve (SI-MV), which is the ratio of the vertical to horizontal MV diameter. Using receiver operating characteristic curve (ROC) analysis for the primary endpoint, the SI-MV cut-off value was determined to be 0.86. The incidence of the primary endpoint was significantly (log-rank P=0.013) higher among patients with a post-procedural SI-MV >0.86 (circular MV morphology) than among those with post-procedural SI-MV ≤0.86 (elliptical MV morphology). Post-procedural SI-MV >0.86 was an independent determinant of the primary endpoint in multivariate analysis (hazard ratio 2.35; 95% confidence interval 1.25–4.42; P=0.0077).

Conclusions: A larger post-procedural SI-MV is associated with increased mid-term adverse clinical events after MV-TEER in patients with FMR.

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: Heart failure with mildly reduced ejection fraction (HFmrEF) is a distinct but relatively understudied phenotype of heart failure. Traditional measures, such as ejection fraction and global longitudinal strain (GLS), have limited prognostic value in HFmrEF, prompting interest in global myocardial work (GMW) as a more comprehensive marker. This study investigated the prognostic utility of GMW in HFmrEF.

Methods and Results: In this retrospective study, 273 patients with HFmrEF diagnosed between 2014 and 2018 were followed for a median of 31 months. Forty-eight patients experienced hospitalization for heart failure (HHF). The global work index (GWI), GLS, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB) use were significantly associated with HHF risk. Univariate Cox regression showed that GWI (hazard ratio [HR] 0.998; 95% confidence interval [CI] 0.997–0.999; P=0.003), global constructive work (HR 0.999; 95% CI 0.998–1.000; P=0.010), ACEi/ARB use (HR 0.464; 95% CI 0.239–0.902; P=0.024), and GLS (HR 1.058; 95% CI 1.004–1.116; P=0.035) were significant predictors of HHF. In multivariable analysis, higher GWI was independently associated with a lower risk of HHF (HR 0.997; 95% CI 0.996–0.998; P=0.001). Notably, GWI ≥850 mmHg% was associated with a significantly lower HHF risk (HR 0.075; 95% CI 0.0288–0.196; P=0.001).

Conclusions: GWI is an independent prognostic marker for HHF in HFmrEF, offering incremental value beyond conventional echocardiographic parameters. However, validation in prospective and multicenter studies is warranted.

Background: Outdoor air pollutants are known to have adverse health impacts, but knowledge of the relationship between exposure to air pollutant mixtures and cardiovascular health (CVH) remains limited.

Methods and Results: We examined the association of air pollutant mixtures with CVH using the American Heart Association’s Life’s Essential 8 (LE8), which is based on 4 health behaviors and 4 biometric health factors. Data from a nationally representative sample of 27,763 adults were analyzed. One-year moving average concentrations of PM₁₀, PM_2.5, SO₂, NO₂, CO, and O₃were estimated through air pollution modeling. CVH was evaluated using LE8 scores (range 0–100), with higher scores indicating superior CVH. The association of a 1-quantile increment in air pollutant mixture with the expected change in LE8 score was evaluated using Quantile g-computation. The mean LE8 score in study participants was 63.7. In the adjusted model, a 1-quantile increment in air pollutant mixture was linked to a 1.67-point (95% confidence interval −2.18, −1.16) decrease in LE8 score. CO, O₃, PM_2.5, and NO₂accounted for 43.7%, 28.7%, 23.9%, and 3.7%, respectively, of the inverse association of the air pollutant mixture with the overall LE8 score.

Conclusions: Our study revealed that long-term exposure to outdoor air pollutants is associated with poor CVH, suggesting the need for supporting policy interventions to reduce air pollutant levels and mitigate their health impacts.

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: Direct oral anticoagulants (DOACs) are commonly used oral anticoagulants for patients with venous thromboembolism (VTE). Sometimes these patients receive concomitant antiplatelet therapy, with limited data supporting the practice. This study investigated the effect of concomitant antiplatelet therapy (CAT) on clinical outcomes in VTE patients treated with anticoagulants.

Methods and Results: The COMMAND VTE Registry-2 is a multicenter registry that enrolled 5,197 consecutive patients with acute symptomatic VTE across 31 centers in Japan between January 2015 and August 2020. After excluding 407 patients without oral anticoagulants, there were 4,790 VTE patients treated with oral anticoagulants. After propensity score matching, 676 patients (338 matched pairs in the CAT and anticoagulant only [AC] groups) were included for analysis. There were no significant differences between the CAT and AC groups in the cumulative 3-year incidence of recurrent VTE (4.9% vs. 7.3%, respectively; P=0.50), major bleeding (9.4% vs. 12.4%, respectively; P=0.36), or stroke (6.7% vs. 4.1%, respectively; P=0.24). However, the cumulative 3-year incidence of clinically relevant non-major bleeding (CRNMB) was significantly higher in the CAT group than in the AC group (17.7% vs. 10.0%; P=0.047).

Conclusions: In a large VTE registry in the DOAC era, concomitant antiplatelet and anticoagulant therapy, compared with anticoagulant alone, was not significantly associated with risks of recurrent VTE, major bleeding, or stroke, but did increase the risk of CRNMB.

Background: In Japan, intravascular lithotripsy (IVL) is indicated during percutaneous coronary intervention (PCI) for calcified lesions when the calcium score assessed by intravascular ultrasound (IVUS) or optical coherence tomography (OCT) is ≥3. This study evaluated the effectiveness of IVL in achieving optimal stent expansion in lesions with an OCT calcium score ≥3, regardless of the IVUS calcium score.

Methods and Results: We retrospectively compared 26 consecutive PCIs in 23 patients who underwent IVL with pre-PCI OCT or optical frequency domain imaging and simultaneous pre- and post-PCI IVUS with 102 patients who underwent PCI without atherectomy but similar imaging protocols. Of all 128 PCIs, 84 with an OCT calcium score ≥3 and a simultaneous IVUS calcium score ≤2 were analyzed. Stent expansion was measured by IVUS. Among the 84 PCIs included in the analysis, 17 were performed using IVL and 67 were performed without atherectomy or IVL (non-IVL group). Stent expansion at the site of maximum superficial calcium was greater in the IVL than non-IVL group (90.9% vs. 84.6%, respectively; P=0.028). The non-IVL group was independently associated with reduced stent expansion at the site of maximum superficial calcium, even after adjusting for IVUS calcium score components (B=−0.817; P<0.001).

Conclusions: Even in calcified lesions with an IVUS calcium score ≤2, IVL was independently associated with favorable stent expansion when the OCT calcium score was ≥3.

Background: Patients with infective endocarditis (IE) on maintenance hemodialysis (HD) have poor outcomes, but contemporary data remain limited.

Methods and Results: We conducted a retrospective analysis using a nationwide Japanese administrative database and identified 12,158 patients hospitalized with IE between 2018 and 2021, including 806 (6.6%) on maintenance HD. The inhospital mortality rate was significantly higher in HD patients (30.0% vs. 13.5%, P<0.05).

Conclusions: Maintenance HD patients with IE had worse outcomes, underscoring the need for early recognition and tailored management in this highrisk group.

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: Atriogenic tethering (AT) is a characteristic feature of the mitral valve in atrial functional mitral regurgitation (AFMR). However, the factors associated with AT are not well known.

Methods and Results: This was a post hoc analysis of REVEAL-AFMR, a retrospective observational study involving patients with moderate or greater AFMR. A stepwise binary logistic regression model was used to identify factors associated with AT. The primary endpoint was a composite of cardiovascular death, heart failure hospitalization, and mitral valve intervention. Of 1,007 patients, 245 (24%) had AT and 762 (76%) did not. Of 15 clinical variables related to AT in AFMR, greater left ventricular end-systolic dimension and left atrial diameter were independently associated with AT. The 3-year rate of freedom from the primary outcome was significantly lower in the group with than without AT (63.2% vs. 71.2%; P=0.002). The risk of the primary outcome was significantly higher in the group with than without AT (adjusted hazard ratio 1.34; 95% confidence interval 1.04–1.74; P=0.026), although the results were inconsistent in the sensitivity analysis using propensity score overlap weighting.

Conclusions: AT was identified in 24% of patients with moderate or greater AFMR. Greater left ventricular end-systolic and left atrial anteroposterior dimensions were factors associated with AT. Among patients with AFMR, those with AT showed a poor prognosis.

Background: Coronary microvascular dysfunction (CMD) is characterized by impaired myocardial flow reserve (MFR) in patients with non-obstructive coronary artery disease (CAD). The real-world incidence of CMD, risk factors for decreased MFR, and characteristics of the two CMD endotypes (classical and endogenous) in this population remain unclear.

Methods and Results: After screening 1,313 patients with suspected or known CAD who underwent ¹³N-ammonia positron emission tomography (PET), 345 with non-obstructive CAD were retrospectively enrolled in the study. Stress/resting myocardial blood flow (MBF) was quantified using ¹³N-ammonia PET. PET-assessed CMD (impaired MFR <2.0) was diagnosed in 60 (17%) patients. Independent predictors of decreased MFR included older age, female sex, anemia, and hypertension; however, these factors accounted for only 32% of the observed variability in MFR. Symptomatic status was not an independent predictor of decreased MFR. Patients with classical CMD (resting MBF <1.3 mL/min/g) had higher summed stress scores and stress/resting coronary vascular resistance, whereas patients with endogenous CMD (resting MBF ≥1.3 mL/min/g) showed female dominance, higher stress MBF, and a higher resting rate-pressure product.

Conclusions: Among patients with non-obstructive CAD, approximately 1 in 5 had PET-assessed CMD. Age, female sex, anemia, and hypertension were independent clinical factors associated with impaired MFR, which explained a limited portion of its variability. Further examination of unidentified or unmeasured factors is warranted.

Background: The diagnostic utility of the exercise electrocardiogram (ECG) in detecting coronary microvascular dysfunction (CMD) remains unclear.

Methods and Results: We analyzed 101 patients without obstructive coronary artery disease (CAD) who underwent the Master double 2-step exercise ECG and invasive coronary physiological assessment. The sensitivity, specificity, positive predictive value, and negative predictive value of ischemic ECG changes for detecting CMD were 0.44, 0.97, 0.85, and 0.84, respectively. The post-test probability of CMD increased from 24.8% to 82.8% with a positive ECG finding.

Conclusions: The Master double 2-step exercise ECG demonstrated high specificity for detecting CMD in patients without obstructive CAD.

Background: Passive leg lifting (PLL) may serve as a simple alternative to simulate exercise stress.

Methods and Results: We evaluated 33 patients with PH who underwent PLL-RHC and exercise right heart catheterization (RHC); 25 patients were classified as having PLL-induced PH (LIPH), demonstrating significant increases in mean pulmonary arterial pressure (mPAP) and mPAP–cardiac output slopes. Strong correlations were observed between PLL-RHC and exercise RHC measurements.

Conclusions: PLL-RHC may represent a simple method for detecting EIPH.

Background: This study evaluated early and mid-term clinical outcomes of surgical correction for anomalous aortic origin of a coronary artery (AAOCA) and expansion of surgical indications beyond current guidelines, particularly for asymptomatic patients with anomalous aortic origin of the right coronary artery (AAORCA).

Methods and Results: Between December 2004 and July 2023, 34 patients underwent surgery for AAOCA. Surgical indications included evidence of myocardial ischemia and high-risk anatomy. AAOCA was assessed pre- and postoperatively using imaging and functional studies. Early and mid-term outcomes were evaluated retrospectively. AAORCA was the predominant type (n=32; 94.1%), and 32 of 34 patients (94.1%) underwent unroofing. Five (14.7%) asymptomatic AAORCA patients had a history of Kawasaki disease. There were no surgical mortalities or coronary artery-related complications. Of 12 patients with symptoms or signs likely related to the coronary artery in the early postoperative period, 2 had persistent symptoms until the last follow-up. During follow-up, 2 patients had suspicious mild coronary stenosis on computed tomography, and 1 had decreased stress perfusion on a myocardial perfusion scan. Among patients with preoperative abnormalities, 92.3% exhibited postoperative functional improvement.

Conclusions: Surgical treatment of AAOCA, primarily through unroofing, is safe and effective, with favorable early and mid-term outcomes. Our findings support consideration of surgery for asymptomatic AAORCA patients with high-risk anatomy due to the potential risk of sudden cardiac events and the substantial benefits of the procedure.

The management of low-density lipoprotein cholesterol (LDL-C) in patients with atherosclerotic cardiovascular disease, particularly those with acute coronary syndrome (ACS), has evolved significantly. Recent evidence emphasizes the importance of early and intensive LDL-C lowering for reducing recurrent cardiovascular events by stabilizing vulnerable plaques. Global guidelines now advocate for more aggressive LDL-C targets, with a common recommendation of <55 mg/dL for high-risk ACS patients. However, regional variations persist in specific target levels, pharmacologic strategies, and follow-up schedules due to differences in healthcare infrastructure, epidemiology, and risk assessment frameworks. Despite guideline updates, achieving recommended LDL-C levels in real-world practice remains challenging, primarily due to issues like healthcare system limitations, patient adherence, and clinical inertia. Some regions in Japan have established local clinical pathways that demonstrate improvements in attainment of LDL-C targets and clinical outcomes. This article explores the current global LDL-C targets and treatment strategies for ACS patients, aiming to enhance the achievement of optimal LDL-C levels and reduce subsequent adverse events.

Background: Right ventricular endomyocardial biopsy may cause conduction disturbances, particularly complete right bundle branch block (CRBBB); however, the impact of using the venous access site remains unclear.

Methods and Results: In 274 patients, CRBBB occurred more frequently with the transfemoral than with the transjugular approach (29.2% vs. 6.7%, P<0.001). The transjugular approach independently reduced CRBBB risk (odds ratio 0.17, P<0.001). Sustained CRBBB was also less frequent (8.3% vs. 1.1%, P=0.007). Major complications, including stroke, pacemaker implantation, and death, were absent.

Conclusions: The transjugular approach reduces CRBBB risk and is a safer option for patients at risk of complete atrioventricular block.

Background: In the presence of a potent P2Y₁₂inhibitor such as prasugrel, the additional clinical antithrombotic benefit of aspirin is unclear. The feasibility of prasugrel monotherapy without aspirin after percutaneous coronary intervention (PCI) has been demonstrated in chronic coronary syndrome, but is yet to be assessed in patients with non-ST elevation acute coronary syndrome (NSTE-ACS) and low anatomical complexity.

Methods and Results: ASET-Japan is a single-arm study investigating the safety of prasugrel 12-month monotherapy with a locally approved dose (loading 20 mg; maintenance 3.75 mg), started immediately after successful PCI using platinum-chromium everolimus-eluting SYNERGY stents. The primary ischemic endpoint is a composite of cardiac death, spontaneous target vessel myocardial infarction, or definite stent thrombosis; the primary bleeding endpoint is Bleeding Academic Research Consortium (BARC) Type 3 and 5 bleeding. ASET-Japan recruited 101 NSTE-ACS patients from 11 Japanese sites. The mean (±SD) age was 69.1±12.3 years and 36.6% had a PRECISE-DAPT score >25. The mean anatomical SYNTAX score was 7.9±4.7. At 1 year, the primary ischemic endpoint occurred in 1 patient (1.0%; cardiac death). Two BARC Type 3a bleeding events occurred (2.0%): 1 due to a gastric ulcer and 1 to a descending colon malignancy.

Conclusions: Low-dose (3.75 mg/day) prasugrel monotherapy started immediately after SYNERGY stent deployment was feasible and safe in selected NSTE-ACS patients.

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.

Cancer is widely recognized as one of the major risk factors for thrombosis, and cancer-associated thrombosis (CAT) is a concept that also encompasses arterial and venous thromboembolism. The risk factors for CAT of clinical concern are assumed to be a complex combination of patient-related factors, the cancer itself, factors related to anticancer therapy, tissue factors expressed on cancer cell membranes, and cytokines released by cancer cells to increase inflammation and coagulation at remote sites. In addition, some anticancer agents are known to damage vascular endothelial cells and cause thrombus formation; early diagnosis and treatment of CAT is recommended because CAT is a significant risk factor for poor prognosis in cancer patients.

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 pathogenesis of aortic aneurysm (AA) is characterized by chronic inflammation of the aortic wall, the associated accumulation of macrophages, and degradation of the extracellular matrix, including elastin. Colchicine (COL) has long been known for its anti-inflammatory effects, so in this study we investigated its effects on AA.

Methods and Results: In vitro, tumor necrosis factor (TNF)-α-stimulated macrophages and vascular smooth muscle cells (VSMCs) were treated with and without COL for 24 h. Unstimulated cells were used as controls. COL significantly reduced interleukin (IL)-1β, TNF-α, monocyte chemotactic protein (MCP)-1, nuclear factor kappa B (NF-κB), matrix metalloproteinase (MMP)-9, and activated caspase-1 in macrophages, and increased lysyl oxdase (Lox) and tissue inhibitor of metalloproteinase (TIMP)-2 expression in VSMCs. In vivo, aged male apolipoprotein E-deficient (ApoE⁻/⁻) mice were infused with angiotensin II (Ang II) for 28 days. The mice received either normal saline (NS) or COL orally. The control group of ApoE⁻/⁻mice did not receive Ang II infusion or treatment. COL significantly suppressed aortic enlargement and reduced AA incidence by preserving elastin and decreasing IL-1β, TNF-α, MCP-1, NLRP3 inflammasome, neutrophil elastase, and myeloperoxidase expression. No significant differences were observed in the enzymatic activities of MMP-2 and MMP-9 between the 2 groups.

Conclusions: The results suggested that COL prevents AA progression in a clinically relevant model and is expected to be a novel preventive agent for AA.

Background: Aortic valve regurgitation (AR) impairs cardiac function, but the underlying mechanisms remain unclear. Vector flow mapping (VFM) enables evaluation of blood flow patterns and energy loss in the left ventricle (LV). This study investigated the effect of AR on LV blood flow patterns, energy loss, and heart failure progression using VFM.

Methods and Results: Forty patients with severe AR undergoing aortic valve replacement (AVR) between January 2016 and March 2018 were included. Echocardiogram-based VFM in apical long-axis and 4-chamber views was performed before and after AVR, with results compared to a control group without valvular diseases (n=21). Preoperative LV energy loss due to an AR jet was significantly higher in patients with AR (median 8.7 J; interquartile range [IQR] 5.7–13.3 J) than in controls (1.7 J; IQR 0.7–2.6 J; P<0.001), and was positively correlated with preoperative serum B-type natriuretic peptide (BNP) concentrations (P=0.029). LV energy loss was not associated with LV systolic function or regurgitant volume, but was significantly affected by AR jet direction. Postoperatively, after AVR, LV energy loss (median 2.0 J; IQR 1.5–2.7 J) decreased to the same level as in the control group.

Conclusions: The regurgitant jet in severe AR increases LV energy loss, which is positively correlated with serum BNP concentrations, indicating that the AR jet contributes to the progression of heart failure through LV energy loss.

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: This study reports on a single center’s experience over 10 years with the frozen elephant trunk (FET) technique and a Japanese prosthesis. FET outcomes were compared among groups according to aortic etiology, acute aortic dissection (AAD), chronic aortic dissection (CAD), and thoracic aortic aneurysm (TAA).

Methods and Results: Between September 2014 and December 2023, 435 patients underwent total arch replacement using the FET technique for AAD, CAD, and TAA. The overall in-hospital mortality rate was 5.1% (13 patients with AAD, 3 with CAD, and 6 with TAA). Perioperative neurological deficits occurred in 5.8% of patients overall (13 patients with AAD, 2 with CAD, and 10 with TAA), and spinal cord injury occurred in 1.1% of patients overall (1 with AAD, 0 with CAD, and 4 with TAA). The respective overall 5- and 7-year survival rates were 88.8% and 83.8% for AAD, 69.2% and 67.4% for TAA, and 83.6% and 83.6% for CAD. The respective 5- and 7-year rates of freedom from distal thoracic aortic reintervention were 78.8% and 71.7% among AAD patients, and 93.7% and 93.7% among TAA patients, and 73.2% at 5 years among CAD patients.

Conclusions: The FET technique using a Japanese prosthesis for thoracic aortic disease has acceptable perioperative and long-term outcomes. Close follow-up is required after FET implantation, especially after repair of AAD and CAD.

Background: Optical coherence tomography (OCT) has the potential to reduce clinical events more effectively than angiography alone, but its penetration rate, clinical utility, and clinical impacts in ST-elevation myocardial infarction (STEMI) remain unknown. We aimed to clarify the relationship between OCT-defined morphology, acute results of primary percutaneous coronary intervention (PCI), and clinical outcomes at 1 year in patients with STEMI.

Methods and Results: This post hoc analysis of the TACTICS registry investigated patients with STEMI who underwent OCT-guided primary PCI. Major adverse cardiovascular events (MACE) were defined as a composite of cardiovascular death, myocardial infarction, heart failure, or ischemia-driven revascularization. Of 1,046 patients with STEMI, 441 (42.2%) underwent OCT-guided PCI. The prevalence of plaque rupture (PR), plaque erosion (PE), and calcified nodule (CN) was 299 (68.3%), 106 (24.2%), and 16 (3.7%), respectively. The cumulative MACE rate was highest in patients with CN (31.2%), followed by those with PR (14.0%) and PE (2.8%; log-rank P<0.0001). Multivariate Cox regression analysis identified CN as the strongest independent predictor of MACE at 1 year (hazard ratio [HR] 8.25; 95% confidence interval [CI] 1.70–40.10; P=0.009), followed by PR (HR 4.82; 95% CI 1.48–15.68; P=0.009).

Conclusions: OCT-guided PCI was performed with a high penetration rate of approximately 40% in patients with STEMI. Lesion morphology may serve as a key predictor of future cardiovascular events.

Background: Because lung fibroblasts play a key role in the pathogenesis of pneumonia, and rho-associated coiled-coil containing protein kinase 1 (ROCK1) is a regulator of lung inflammation, this study studied the action of ROCK1 on lung fibroblast functions under pneumonic conditions.

Methods and Results: WI-38 fibroblasts were stimulated with lipopolysaccharide (LPS) in vitro. A mouse model of pneumonia was produced by LPS induction. IP, Co-IP, and protein stability assays were used to confirm the ubiquitin-specific protease 33 (USP33)/ROCK1 relationship. RIP, Me-RIP, and mRNA stability assays were used to validate the methyltransferase-like 3 (METTL3)/ROCK1 relationship. In LPS-inducible WI-38 cells and serum samples of patients with pneumonia, ROCK1, USP33, and METTL3 levels were increased. ROCK1 deficiency attenuated LPS-evoked apoptosis, inflammation, and oxidative stress in WI-38 fibroblasts and BEAS-2B cells, and also diminished macrophage M1 polarization. Mechanistically, USP33 stabilized ROCK1 protein through deubiquitination, and METTL3 stabilized ROCK1 mRNA in an m6A-IGF2BP1-dependent mode. Depletion of USP33 or METTL3 mitigated LPS-evoked WI-38 cell injuries and macrophage M1 polarization by downregulating ROCK1. Moreover, ROCK1 depletion ameliorated LPS-evoked lung injuries in a pneumonia mouse model.

Conclusions: Our findings suggested that ROCK1 upregulation induced by USP33 and METTL3 affected LPS-evoked dysfunction in WI-38 fibroblasts and lung injuries in pneumonic mice, providing promising therapeutic targets for pneumonia.

Background: Anthracycline-induced cardiotoxicity (AIC) poses significant challenges due to its severe adverse effects, limiting the use of anthracycline drugs (ATC). Early detection and intervention are pivotal, yet current diagnostic methods lack sensitivity.

Methods and Results: In a prospective animal study, 20 rabbits were administered adriamycin weekly and underwent cardiac magnetic resonance (CMR) scanning every 2 weeks. Ventricular function and myocardial metabolite content were assessed. Using a linear mixed model, we determined the earliest CMR-sensitive time and diagnostic thresholds for AIC detection via proton magnetic resonance spectroscopy (¹H-MRS). Results showed that Lipid1 increased significantly earlier at week 6 compared to the decreased left ventricular ejection fraction (LVEF) at week 8 (P<0.05). ROC analysis revealed that a Lipid1 cutoff value of 2.60 had the best diagnostic accuracy for AIC at week 6, with an area under the curve of 0.745, specificity of 0.71, and sensitivity of 0.80 (95% CI: 0.575–0.916). Lipid1 also demonstrated a moderately negative correlation with LVEF (r=–0.418, P<0.01).

Conclusions: ¹H-MRS-detected Lipid1 increased at week 6 after anthracycline injection, offering earlier diagnosis of AIC compared to conventional LVEF biomarkers.

Background: Venous thromboembolism (VTE) is a serious complication following spine surgery for metastatic tumors. This study used the US Nationwide Readmissions Database to identify predictors of VTE and its associations with outcomes.

Methods and Results: Data between 2016 and 2020 were retrospectively reviewed. Patients aged ≥18 years undergoing non-emergency surgery for spinal metastasis were included in the analysis. Multivariable regression analysis was used to assess associations of VTE with in-hospital outcomes and 30- and 90-day readmissions, as well as demographic and clinical factors associated with VTE occurrence during the index admission. In all, 2,706 patients were included in the analysis (mean age 63.6 years; 1,435 [53%] male). Of all patients, 126 (4.7%) developed VTE during the index admission. After adjustment, VTE was significantly associated with an increased risk of in-hospital mortality (adjusted odds ratio [aOR] 5.34; 95% confidence interval [CI] 2.38–11.96) and 30-day readmission (aOR 2.06; 95% CI 1.33–3.19). Delays from admission to surgery (aOR 1.88; 95% CI 1.27–2.79) and a Charlson Comorbidity Index score ≥4 (aOR 3.11; 95% CI 1.60–6.04) were independently associated with an increased risk of VTE.

Conclusions: In patients undergoing surgery for spinal metastasis, postoperative VTE is associated with higher in-hospital mortality and 30-day readmission risks. A Charlson Comorbidity Index score ≥4 and delayed surgery are independently associated with greater risk of VTE.

Background: Predicting the bleeding risk during anticoagulation therapy is a key clinical challenge in patients with venous thromboembolism (VTE). However, there is no established prediction score for major bleeding (MB) in patients with VTE treated with direct oral anticoagulants (DOACs).

Methods and Results: Using the COMMAND VTE Registry-2, which enrolled 5,197 patients with acute symptomatic VTE between 2015 and 2020 among 31 centers in Japan, we investigated the risk factors for MB beyond 7 days and within 180 days in patients who received DOACs. A prediction score was developed in the derivation cohort (n=1,618), and prediction performance was evaluated in the validation cohort (n=809). Multivariate logistic regression analysis in the derivation cohort identified factors associated with MB. Based on β coefficients for each factor, the prediction score assigned 2 points to active cancer, history of MB, and thrombocytopenia, and 1 point to creatinine >1.2 mg/dL and anemia, summing them. The C statistic of the prediction score was 0.74 (95% confidence interval [CI] 0.68–0.80) in the derivation cohort and 0.74 (95% CI 0.67–0.81) in the validation cohort (P=0.98). When a cut-off value of 3 was used for the risk score, the sensitivity and specificity were 56.1% and 79.2%, respectively.

Conclusions: The prediction score developed for MB during DOAC therapy (COMMAND-BLEED score) could be clinically useful for decision-making regarding anticoagulation strategies with DOACs.

Background: Pregnant women are at high risk of venous thromboembolism (VTE), which is one of the important causes of maternal death.

Methods and Results: Using a Japanese nationwide hospital administrative database, we identified 410 pregnant women who were admitted to hospital with VTE between April 2008 and September 2023. We evaluated clinical characteristics and outcomes. Of the 410 women, 110 (26.8%) developed pulmonary embolism (PE). The median week of pregnancy at the time of VTE onset was 31 weeks. The incidence of VTE exhibited a bimodal distribution: 126 (30.7%) women developed VTE in the first trimester (before 14 weeks gestation) and 236 (57.6%) developed VTE in the third trimester (after 28 weeks gestation). PE was more common in the later stages of pregnancy. Regarding anticoagulation therapy, 374 (91.2%) women received unfractionated heparin and 18 (4.4%) received low-molecular-weight heparin. During the 6-month follow-up period, 17 (4.1%) women experienced VTE recurrence and 3 (0.7%) developed bleeding events, including intracranial hemorrhage and gastrointestinal bleeding. During hospitalization, 4 (1.0%) women died, 3 of whom had a history of surgical procedures, including cesarean section and hysterectomy.

Conclusions: This large nationwide database revealed important clinical features and outcomes of pregnancy-associated VTE, highlighting its bimodal incidence and the need for early vigilance, benefiting cardiologists and obstetricians.

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.

Iron is an essential requirement for normal cellular function and oxygen transport. Deficiency of iron, due to suboptimal intake, blood loss, malabsorption or maldistribution is the most common nutrient deficiency worldwide. Iron deficiency (ID) has traditionally been ignored until anemia develops. Amongst patients with cardiovascular (CV) disease, ID is common and is associated with worse symptoms, poorer quality of life, and a worse prognosis. However, the criteria used to define ID in studies and international guidelines are inconsistent and lack universal acceptance. Accordingly, we review the various criteria used to define ID in patients with CV disease, discuss how these might have influenced the results of observational studies and randomized trials and suggest areas for future research.

Background: Several cross-sectional studies have implicated gut dysbiosis caused by an abundance of oral commensals in stroke, but the effect on long-term prognosis is still unknown. Therefore, we longitudinally investigated oral pathobionts in the gut and their clinical relevance to stroke.

Methods and Results: We analyzed the salivary and gut microbiomes collected from 189 acute stroke and 55 non-stroke subjects, and found that Streptococcus anginosus was significantly more abundant in both the saliva (median [IQR], 0.01 [0.00–0.14] vs. 0.00 [0.00–0.03], P=0.02) and gut (0.09 [0.00–0.28] vs. 0.00 [0.00–0.02], P<0.001) of the stroke patients compared with their non-stroke counterparts. Network analysis revealed S. anginosus as a central hub in gut dysbiosis. After adjusting for vascular risks, S. anginosus (odds ratio 1.20, 95% confidence interval 1.06–1.36, P<0.01), Anaerostipes hadrus (0.82, [0.73–0.93], P<0.01), and Bacteroides plebeius (0.86, [0.86–0.93], P=0.01) in the gut were independent predictors of stroke. Longitudinally, S. anginosus in the gut was significantly associated with increased rates of death and major cardiovascular events (P=0.04; log-rank test), whereas A. hadrus and B. plebeius were not (P=0.45 and P=0.19). After adjusting for vascular risks, S. anginosus in the gut was a residual risk for increased rates of death and major cardiovascular events (hazard ratio 4.78, 95% confidence interval 1.08–21.18, P=0.04)

Conclusions: S. anginosus in the gut may increase the risk of stroke and a poor prognosis.

Myocarditis is a heterogeneous disease with diverse etiologies and clinical trajectories. Traditionally, its diagnosis has been guided by the Dallas criteria, which focus on histopathological features. Clinically, myocarditis is categorized as acute or chronic based on the duration since symptom onset. However, recent expert consensus, particularly in Western countries, has redefined myocarditis as either acute myocarditis or chronic inflammatory cardiomyopathy, including inflammatory dilated cardiomyopathy, reflecting advancements in viral genome analysis and histopathology. In 2023, the Japanese Circulation Society proposed the concept of chronic active myocarditis, a high-risk phenotype characterized by persistent inflammation and ongoing cardiomyocyte injury. The transition from acute myocarditis to its chronic phase involves complex immune mechanisms, with sustained myocardial inflammation driving ventricular remodeling and progression to heart failure. Cardiac magnetic resonance imaging and endomyocardial biopsy remain pivotal diagnostic modalities, though their diagnostic yield varies according to disease phase. Management strategies focus on heart failure treatment, arrhythmia control, and, in select cases, immunosuppressive therapy, particularly for virus-negative inflammatory cardiomyopathy. Although antiviral therapy has shown promise, its clinical efficacy remains uncertain. Given the evolving understanding of the chronic phase of myocarditis, further research is warranted to refine the diagnostic criteria and optimize personalized therapeutic strategies. This review gives a comprehensive overview of the pathophysiology, classification, and management of chronic myocarditis, with an emphasis on emerging disease concepts and their clinical implications.

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: 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: The antiplatelet effect of prasugrel for acute ischemic stroke or transient ischemic attack (TIA) remains unclear. This study compared platelet reactivity between prasugrel and clopidogrel, considering cytochrome P450 family 2 subfamily C member 19 (CYP2C19) gene polymorphisms (extensive metabolizers [EM], intermediate metabolizers [IM], and poor metabolizers [PM]), in patients with acute large artery atherosclerosis (LAA) or high-risk TIA.

Methods and Results: In this multicenter open-label randomized controlled study, patients with acute LAA or high-risk TIA received prasugrel or clopidogrel with aspirin. The primary endpoint was platelet reaction units (PRU) 5 days after the start of drug administration, stratified according to CYP2C19 polymorphism. In all, 176 patients participated (88 in each group). Compared with the clopidogrel group, PRU on Day 5 in the prasugrel group were significantly lower in the overall population (adjusted mean 136.0 vs. 169.9; estimated difference −33.9; 95% confidence interval [CI] −49.0, −18.8), EM group (118.5 vs. 144.8; estimated difference −26.2; 95% CI −48.0, −4.4), and IM group (140.3 vs. 173.1; estimated difference −32.8; 95% CI −56.6, −9.0), and tended to be lower in the PM group (164.7 vs. 196.2; estimated difference −31.6; 95% CI −68.3, 5.1). The prevalence of new infarct lesions was comparable between the prasugrel and clopidogrel groups, as was the incidence of adverse events (30.7% vs. 26.1%, respectively) and bleeding events up to Day 5 of administration.

Conclusions: In patients with acute LAA or high-risk TIA, prasugrel resulted in stable inhibition of platelet aggregation 5 days after starting drug administration compared with clopidogrel, regardless of CYP2C19 polymorphisms.

Background: This study compared procedural complications, patency, and adverse events between a stent strategy and drug-coated balloon (DCB) treatment after using the JETSTREAM atherectomy device for severely calcified femoropopliteal (FP) lesions.

Methods and Results: We retrospectively analyzed multicenter data from 588 patients who underwent endovascular therapy for severely calcified de novo FP lesions between April 2018 and December 2023 at 8 centers in Japan. Patients were categorized into 2 groups based on the revascularization method: stent strategy and DCB after JETSTREAM atherectomy. Propensity score matching (PSM) was performed to compare primary patency, clinically driven target lesion revascularization (CD-TLR), and the occurrence of acute limb ischemia (ALI)/major amputation at 1 year. After PSM, 82 matched pairs of patients were identified, with no significant intergroup differences in baseline characteristics. The rates of primary patency, CD-TLR, ALI, and major amputation were similar between the 2 groups. However, the rate of distal embolization was significantly higher in the DCB after JETSTREAM group. (18.3% vs. 1.2%; P<0.001) Baseline characteristics had no interaction effects on the association between the 2 strategies and the 1-year restenosis risk.

Conclusions: DCB after JETSTREAM atherectomy demonstrated comparable safety, except for distal embolization, and high efficacy in patients with severely calcified FP lesions, suggesting that it may be an alternative revascularization method to the stent strategy.