Background: There are limited data on the use of whole-exome sequencing (WES) to diagnose severe hypertriglyceridemia. Our aim was to identify candidate genes linked to triglyceride levels via a genome-wide association study (GWAS) and to recruit participants with severe hypertriglyceridemia for WES to assess allelic variants in the candidate genes.

Methods and Results: A GWAS was conducted involving 120,140 participants to identify lead loci associated with blood triglyceride levels. Following the identification of these lead loci, WES was performed on DNA samples from 29 participants with hypertriglyceridemia whose triglyceride levels exceeded 800 mg/dL to assess variations in the corresponding genes. In the GWAS of 120,140 participants, the apolipoprotein A5 (APOA5) locus on chromosome 11 showed the strongest association with blood triglyceride levels (lead single nucleotide polymorphism [SNP] rs2075291; P=3.07×10⁻¹⁰⁸), along with 5 independent SNPs (most significant P=7.84×10⁻¹⁶⁷). Other key loci included BUD13 homolog (BUD13; P=2.73×10⁻⁶²), glucokinase regulator (GCKR; P=2.63×10⁻²⁴), and lipoprotein lipase (LPL; P=1.50×10⁻¹¹). WES in 29 hypertriglyceridemia patients identified additional genes, including ALDH1A2, APOC1, LPL, RGS7, and SIK3, showing significant allele frequency variations and potential roles in lipid metabolism.

Conclusions: Our study confirms the role of known genetic loci in triglyceride metabolism and hypertriglyceridemia while uncovering novel loci, offering new perspectives on lipid regulation and potential avenues for therapeutic advancements.

Background: The Apple Watch (AW) can record single-lead electrocardiograms (ECGs) and has been investigated for arrhythmia detection. In this study we evaluated its accuracy in identifying the origin of premature ventricular contractions (PVCs) vs. standard 12-lead ECGs.

Methods and Results: A total of 7 patients with PVCs were assessed using both 12-lead and AW ECG recordings. The QRS polarity observed in the AW recordings was consistent with that of the standard ECGs in most cases, demonstrating its utility in estimating three distinct PVC origins.

Conclusions: The AW holds potential as an auxiliary tool for PVC origin assessment, contributing to arrhythmia management in clinical practice.

Background: The optimal treatment strategy for patients with coronary chronic total occlusion (CTO) and left ventricular systolic dysfunction (LVSD) remains unclear. This study investigated the long-term outcomes of percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), and medical therapy (MT) in this specific patient cohort.

Methods and Results: This retrospective cohort study included 987 consecutive patients with CTO and LVSD who met the inclusion criteria and underwent either CTO-PCI (n=277), CTO-CABG (n=222), or CTO-MT (n=488) between 2014 and 2020. The primary outcome was all-cause mortality during follow-up. Secondary endpoints were major adverse cardiac and cerebrovascular events (MACCE) and their components, including cardiovascular mortality, myocardial infarction (MI), stroke, unplanned revascularization, and hospitalization for heart failure. During a median follow-up of 5.3 years, 232 (23.51%) patients died from any cause. In the unadjusted analysis, CTO-MT was associated with worse long-term survival prospects. After inverse probability of treatment weighting and variable adjustment, CTO-PCI and CTO-CABG demonstrated significant reductions in the long-term risks of all-cause and cardiovascular mortality. Notably, CTO-CABG was associated with the lowest long-term risks of MACCE, MI, unplanned revascularization, and hospitalization for heart failure.

Conclusions: For patients with CTO and LVSD, successful CTO revascularization significantly improved long-term survival compared with CTO-MT. CTO-CABG can be regarded as the optimal treatment modality for better long-term prognosis.

Background: Fabry disease is a hereditary metabolic disorder caused by a decrease in or deficiency of the lysosomal enzyme α-galactosidase A. Enzyme replacement therapy or pharmacological chaperone therapy can improve prognosis, especially in patients in the early phase of cardiac involvement. Longitudinal strain (LS) evaluated using speckle tracking echocardiography can detect early contractile dysfunction. However, there have been no reports of LS in Japanese Fabry disease patients.

Methods and Results: We recruited 56 patients with Fabry disease (22 men, 34 women) who were followed up at Jikei University Hospital. Fifty-eight control subjects without overt cardiac diseases were also included in the study. We evaluated LS in each patient, and the values of each of the 17 segments of the left ventricle (LV) were averaged, and global LS (GLS) was also calculated. GLS was significantly worse in Fabry disease patients without LV hypertrophy than in control subjects (−18.5±2.8% vs. −20.4±1.6%; P<0.05). In addition, Fabry disease patients without LV hypertrophy had significantly worse lateral LS (−16.4±5.0% vs. −19.3±1.8%; P<0.05), basal LS (−16.5±3.2% vs. −18.5±1.7%; P<0.05), and mid LS (−18.7±1.7% vs. −20.8±1.6%; P<0.05) than control subjects.

Conclusions: These results suggest that early contractile dysfunction in Fabry disease can be observed using GLS, lateral LS, basal LS, and mid LS, even without LV hypertrophy.

Background: The angiography-derived non-hyperemic pressure ratio (angioNHPR) is a novel index of NHPR based on artificial intelligence (AI) that does not require pressure wires. We investigated the diagnostic accuracy of angioNHPR for detecting hemodynamically relevant coronary artery disease.

Methods and Results: In this retrospective single-center study, angioNHPR was assessed using the invasive NHPR as the reference standard. An angioNHPR ≤0.89 was defined as indicative of physiologically significant stenosis. Two angiographic projections ≥30° difference in angulation were selected. The lumen and centerline were automatically segmented by the prototype software, allowing for the calculation of the angioNHPR. We assessed 222 vessels from 178 patients. The accuracy of angioNHPR was 76.6% (95% confidence interval [CI] 70.4–82.0), with sensitivity 66.2% (95% CI 54.0–77.0), specificity 81.5% (95% CI 74.3–87.3), positive predictive value 62.7% (95% CI 53.6–70.9), and negative predictive value 83.7% (95% CI 78.6–87.7). The angioNHPR showed good correlation with invasive NHPR (r=0.72; 95% CI 0.64–0.77; P<0.001), and the agreement between angioNHPR and invasive NHPR was −0.01 (limits of agreement: −0.13, 0.11). The area under the curve (AUC) of angioNHPR was 0.81 (95% CI 0.75–0.86), which was significantly higher than that of 2-dimensional quantitative coronary angiography (AUC 0.69; 95% CI 0.62–0.75; P=0.007).

Conclusions: AI-based angioNHPR demonstrates good diagnostic performance using invasive NHPR as the reference standard.

Medicine, and human healing more generally, have been constantly evolving for millennia as part of humanity’s persistent efforts to heal its injuries and diseases, to maintain wellbeing, and to delay the inevitable: death. The philosophy underlying medicine has always been closely intertwined with the prevailing ideas in each historical period. Prejudices, religious beliefs, even magical herbs, as well as rational thought and advanced sciences, make up the fabric of over 2,000 years of western medicine. Hippocrates (460–377 BC), a physician from ancient Greece, is considered the father of western medicine. Almost 2,000 years later, Andreas Vesalius (1514–1564), by being the first to explore anatomical dissections of humans, significantly challenged the views of Galen, thus ushering in modern medicine, which, by the mid-19th century, had evolved into clinical medicine, a holistic approach that remains relevant today. The rapid advances in artificial intelligence, and more broadly in digital health, are shifting clinical medicine towards a new perspective, that of metaclinical medicine, where human doctors will need to work closely with non-human physicians, delegating a significant part of their traditional role in diagnosis and treatment. This article outlines the existing realities regarding the role of artificial intelligence in diagnosing various diseases, and speculates on the collaboration between human and non-human physicians in the metaclinical era.

Background: Accurate prediction of short-term mortality in patients with acute pulmonary embolism (PE) is critical for optimizing treatment strategies and improving patient outcomes. The Pulmonary Embolism Severity Index (PESI) is the current reference score used for this purpose, but it has limitations regarding predictive accuracy. Our aim was to develop a new short-term mortality prediction model for PE patients based on deep learning (DL) with multimodal data, including imaging and clinical/demographic data.

Methods and Results: We developed a novel multimodal deep learning (mmDL) model using contrast-enhanced multidetector computed tomography scans combined with clinical and demographic data to predict short-term mortality in patients with acute PE. We benchmarked various machine learning architectures, including XGBoost, convolutional neural networks (CNNs), and Transformers. Our cohort included 207 acute PE patients, of whom 53 died during their hospital stay. The mmDL model achieved an area under the receiver operating characteristic curve (AUC) of 0.98 (P<0.001), significantly outperforming the PESI score, which had an AUC of 0.86 (P<0.001). Statistical analysis confirmed that the mmDL model was superior to PESI in predicting short-term mortality (P<0.001).

Conclusions: Our proposed mmDL model predicts short-term mortality in patients with acute PE with high accuracy and significantly outperforms the current standard PESI score.

Background: Transcatheter closure of paravalvular leak (PVL) has become an established treatment for patients at prohibitive surgical risk. However, few studies have examined the feasibility of transcatheter closure using Amplatzer occluders in Japanese patients with mitral PVL.

Methods and Results: Twelve patients (mean [±SD] age 78±7 years) with heart failure, hemolytic anemia, or both after surgical mitral prosthetic valve replacement (mechanical valve, 75%) underwent transcatheter PVL closure with Amplatzer Vascular Plug II (AVP-II)/Amplatzer Duct Occluder II (ADO-II) between 2014 and 2021 at Toho University Ohashi Medical Center. We examined procedural, in-hospital, 30-day, and 1-year outcomes. All procedures were performed under general anesthesia using an antegrade transseptal approach, and the procedures were successful in all cases. The mean (±SD) number of Amplatzer occluders deployment per patient was 2.9±1.1, and in 2 patients the combined use of ADO-II was required. The mitral PVL grade decreased notably from 3+ to 1+, with residual PVL being mild or absent in 9 patients. There were no all-cause mortalities, major adverse events, or device-related complications at the 30-day follow-up. At 1 year, all-cause mortality was 16.7% and 3 (25%) patients required reintervention because of the recurrence of clinical symptoms.

Conclusions: Our findings suggest that transcatheter PVL closure with AVP-II/ADO-II can be feasible and safe in Japanese patients with mitral PVL, leading to satisfactory early clinical outcomes.

Background: Global coronary flow reserve (G-CFR) impairment represents coronary microvascular dysfunction (CMD) and correlates with poor prognosis. Hyperemic coronary flow is reduced in conventional CMD, but normal or mildly reduced with elevated resting flow in endogenous-type CMD (E-CMD). This retrospective study assessed the prognostic value of post-percutaneous coronary intervention (PCI) CMD, focusing on E-CMD.

Methods and Results: We included 320 chronic coronary syndrome (CCS) patients undergoing PCI and post-PCI phase contrast cine-cardiac magnetic resonance imaging (CMR). Major adverse cardiac and cerebrovascular events (MACCE) were evaluated, considering the presence of post-PCI CMD and E-CMD based on G-CFR and resting myocardial flow assessed by coronary sinus flow using CMR. CMD was defined as G-CFR <2.0 and classified as E-CMD or non-E-CMD. Post-PCI CMD was observed in 43.4% of patients, 63.3% exhibiting E-CMD. During a median 2.5-year follow-up, MACCE occurred in 26 (8.1%) patients, more often in those with CMD (11.5% vs. 5.5%; P=0.063). MACCE incidence was higher in E-CMD than non-E-CMD and non-CMD (14.8% vs. 5.9% and 5.5%, respectively; P=0.027). Kaplan-Meier analysis revealed worse prognosis in E-CMD (P=0.025). Cox proportional hazards modeling revealed that E-CMD independently predicted MACCE (hazard ratio 3.24; 95% confidence interval 1.47–7.14; P=0.004).

Conclusions: Post-PCI CMD, particularly E-CMD, was significantly associated with worse outcomes in CCS patients. Post-PCI CMD evaluation could guide therapeutic strategies for CCS patients.

Background: With advances in treatment, the prognosis for pregnancies complicated by pulmonary arterial hypertension (PAH) has been improving. However, PAH-related maternal mortality remains high compared with that due to other cardiovascular diseases. The specifics of PAH-related maternal deaths under advanced medical standards are not well understood.

Methods and Results: We used the maternal death registration system established by the Japan Association of Obstetricians and Gynecologists and reviewed 6 PAH-related maternal deaths from 2010 to 2022. All women were initially diagnosed with PAH during pregnancy or immediately after childbirth. The diagnosis of PAH tended to be delayed because symptoms were not reported to healthcare providers and/or a different disease was diagnosed. Cardiogenic shock occurred antepartum in 1 woman and during delivery or within 7 days after delivery in the other 5 women. Four women were resuscitated and started on extracorporeal membrane oxygenation. Pulmonary vasodilators were initiated in 4 women, with a median duration of 8 days from PAH diagnosis to starting medication. Right heart failure was the most common cause of maternal death, with a median duration of 16 days from PAH diagnosis to maternal death.

Conclusions: All PAH-related maternal deaths occurred in women who were diagnosed with PAH after pregnancy. Diagnosing PAH and initiating pulmonary vasodilators takes considerable time, highlighting the importance of early diagnosis and early treatment.

Background: Among patients with functional mitral regurgitation (FMR), responders to transcatheter mitral edge-to-edge repair (TEER) remain unclear. We investigated whether the slope of the preload recruitable stroke work relationship (M_w; calculated as stroke work / [EDV − k × EDV + {1 − k} × LV wall], where EDV is end-diastolic volume, k is a constant, and LV wall is the volume of the left ventricular wall) could predict rehospitalization in FMR patients after TEER.

Methods and Results: M_wwas calculated for 24 FMR patients using echocardiography. The median left ventricular ejection fraction was 27% and the median M_wwas 32. Over a 498-day median follow-up period, 38% of patients were rehospitalized for heart failure, and only M_whad a high area under the curve in time-dependent receiver operating characteristic analysis.

Conclusions: M_wis an effective predictor for rehospitalization in FMR patients after TEER.

Cardiovascular diseases (CVD) have imposed a substantial burden on population health and society. In Japan, the National Plan for the Promotion of Measures Against Cerebrovascular and Cardiovascular Disease, grounded in national legislation, seeks to improve the quality of care and standardize treatment for cerebrovascular disease and CVD. The plan emphasizes the need to develop standardized systems for collecting and disseminating medical information, as well as promoting data-driven research. The Japanese Registry Of All cardiac and vascular Diseases (JROAD) was launched by the Japanese Circulation Society to assess the clinical activities of institutions nationwide that have a dedicated cardiovascular inpatient service. Information from participating facilities is accumulated, and a database is constructed by linking Diagnosis Procedure Combination data, which includes patient characteristics and clinical data. Using this real-world data is expected to generate high-quality evidence, leading to a better understanding of CVD, improvements in the quality of care and clinical outcomes, and the implementation of effective health policies, including the appropriate allocation of medical resources and the reduction of medical costs. Ultimately, these efforts aim to extend the life span and healthy life expectancy. This design paper outlines the overall concept of the JROAD investigation in cardiovascular care. In addition, it summarizes representative CVD data, reviews the literature on the quality of care, and describes the prospects of the investigation.

Anticoagulant therapy is a drug therapy that inhibits the formation of blood clots. Although anticoagulants are effective in preventing thromboembolism, they also carry the risk of bleeding, so they must be managed carefully, taking both efficacy and safety into account. Evidence regarding the effectiveness and safety of each anticoagulant has already accumulated through many large clinical trials and post-marketing surveillance. However, when making decisions in clinical practice, it is necessary to always take into consideration differences in patient populations between clinical trials and actual clinical practice, as well as differences in historical background. (For example, there are differences in antiplatelet drugs and coronary artery interventions that were mainly used in each era.) In this review we discuss the effectiveness and safety of currently used anticoagulants, focusing on different patient backgrounds and points to keep in mind regarding their proper use, based on the latest reports in Asian populations, especially Japanese people, over the past 1–2 years.

Background: Cardiac malformations are a major component of heterotaxy syndrome and result in significant mortality and morbidity. This multicenter nationwide Japanese study evaluated mortality and morbidity after initial surgical palliation for patients with heterotaxy syndrome and determined predictors for mortality and morbidity among patients enrolled in the study.

Methods and Results: The Japanese Congenital Cardiovascular Surgery Database (JCCVSD) collects clinical data from 119 domestic institutions specializing in congenital heart disease, covering almost all major congenital heart surgery programs in Japan. Clinical data on preoperative, operative, and postoperative characteristics and survival data within 30 and 90 days were available from the JCCVSD database. Of the 561 patients with heterotaxy syndrome who underwent any of 8 specific initial cardiovascular surgeries, 45 (8.2%) and 75 (13.4%) had died at 30 and 90 days, respectively. Preoperative emergency transport, type of heterotaxy syndrome, low hospital volume, the repair of total anomalous pulmonary vein connection, and the repair of a common atrioventricular valve were identified as significant predictive factors for operative mortality.

Conclusions: Improvements in some medical circumstances, such as fetal diagnosis and the patient transport system, will be needed to improve outcomes for severely ill patients with heterotaxy syndrome. This study describes early outcomes for the largest number of main cardiovascular surgeries to date in infants with heterotaxy syndrome.

Background: Sleep apnea (SA), subjective sleep duration (SSD), and objective sleep duration (OSD) were reported as risk factors for atrial fibrillation (AF). However, the association between AF and the combination of SA and OSD has not been clarified. Nor has a mismatch between SSD and OSD been investigated.

Methods and Results: We assessed SA with polysomnography, OSD with actigraphy, and SSD in patients who underwent radiofrequency catheter ablation for persistent AF. We investigated associations among SA, OSD, OSD×3% oxygen desaturation index (3%ODI), and AF recurrence, considering SSD–OSD (i.e., the difference between SSD and OSD) and OSD. Seventy of 94 (74.4%) participants had moderate-to-severe SA (apnea-hypopnea index [AHI] ≥15). Participants were classified into OSD tertiles. Participants in Tertile 3 (mean OSD: 7.3 h) had decreased SSD–OSD (0.0 h) with increased Stage N1 sleep. Over 27.6 months, 10 AF recurrences occurred in 51 participants without treatment for SA. AHI ≥20 and OSD Tertile 3 were associated with AF recurrence (hazard ratios 5.7 [95% confidence interval 1.1–24.7] and 10.3 [95% confidence interval 1.2–88.4], respectively). Participants with AF recurrence had a higher OSD×3%ODI.

Conclusions: SA and long OSD were predictors of recurrent AF through long exposure to intermittent hypoxia during sleep. SSD–OSD was low in patients with long OSD, possibly because of decreased sleep quality.

Background: Although the MADIT-ICD benefit score (MBS) helps select suitable implantable cardioverter defibrillator (ICD) candidates, optimal indicators for cardiac resynchronization therapy (CRT) remain uncertain. Evaluating the applicability of the MBS in Japanese CRT patients is imperative.

Methods and Results: This multicenter study assessed the cumulative incidence of ventricular tachycardia/fibrillation (VT/VF) and non-arrhythmic mortality (AM) in CRT patients grouped according to potential benefit (lowest, highest, and intermediate). Among 400 primary prevention patients (mean age 65 years, 76% male), VT/VF occurred in 4 (7%), 68 (24%), and 14 (23%) patients in the lowest-, intermediate-, and highest-benefit groups, respectively (P=0.027), over a median follow-up of 34 months. Non-arrhythmic death was observed in 15 (25%), 91 (33%), and 9 (15%) patients in the lowest-, intermediate-, and highest-benefit groups, respectively (P=0.025). Multivariate analysis identified VT/VF score ≥7 (hazard ratio [HR] 2.14; 95% confidence interval [CI] 1.09–4.19; P=0.027) as a significant VT/VF predictor. The presence of left bundle branch block (HR 0.51; 95% CI 0.29–0.92; P=0.025) was associated with a reduced risk of VT/VF events. Non-AM score ≥3 (HR 1.70; 95% CI 1.01–2.88; P=0.047), systolic blood pressure <100 mmHg (HR 1.84; 95% CI 1.25–2.70; P=0.002), and estimated glomerular filtration rate <30 mL/min/1.73 m²(HR 1.98; 95% CI 1.23–3.20; P=0.005) were significant predictors of non-arrhythmic death.

Conclusions: The MBS can identify suitable candidates for CRT-D among Japanese individuals.

Background: Vascular complications are common and can be fatal even after successful decannulation in patients with peripherally cannulated veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Therefore, we aimed to accurately determine the incidence of arterial complications assessed by Duplex ultrasound following peripheral VA-ECMO decannulation. In addition, we investigated the predictors of severe complications requiring intervention.

Methods and Results: We retrospectively reviewed 1,350 adult patients who underwent ECMO between January 2012 and April 2023. Of 839 patients treated with peripherally cannulated VA-ECMO, 596 were successfully weaned off and 212 underwent Duplex ultrasound for final analysis. The primary outcome was arterial complications requiring vascular intervention. Thirty-three (15.6%) patients experienced such complications after decannulation. Acute limb ischemia due to thrombotic occlusion was the most common complication, occurring in 23 (10.8%) patients, followed by stenosis (3.8%), pseudoaneurysm (3.8%), arteriovenous fistula (0.9%), and dissection (0.9%). No significant differences in complication rates were found between the percutaneous and surgical decannulation groups in the propensity score-matched population (12.7% vs. 15.9%, respectively; P=0.799). Multivariable analysis revealed disseminated intravascular coagulation (DIC; odds ratio 2.6; 95% confidence interval 1.17–5.69; P=0.019) as the only predictor of arterial complications after decannulation.

Conclusions: Arterial complications requiring vascular intervention frequently occur following successful weaning from VA-ECMO regardless of the decannulation strategy. In this setting, DIC appears to be associated with an increased rate of arterial complications.

Takayasu arteritis (TAK) is classified as a large vessel vasculitis and often causes vascular stenosis, occlusion, and aneurysm formation. Although the principal treatment for TAK involves suppressing inflammation with glucocorticoids, the emergence of biological disease-modifying antirheumatic drugs has considerably changed the treatment landscape of TAK in recent years. Several biological disease-modifying antirheumatic drugs, such as tocilizumab (TCZ), have shown promising effects on TAK in clinical studies. Cardiologists and cardiovascular surgeons encounter patients receiving these drugs who require catheterization, endovascular treatment, or cardiovascular surgery. However, in patients treated with glucocorticoids and TCZ, there needs to be greater awareness of more complications than usual after surgery, such as delayed wound healing, systemic infection, and surgical site infection. In addition, in patients receiving TCZ, inflammatory markers, such as C-reactive protein, may not increase when complications arise from infection. Unfortunately, there are no guidelines or solid evidence that have clearly defined the optimal perioperative treatment strategy for patients with TAK who require cardiovascular surgery. This article reviews the evidence and our recent experience supporting the perioperative use of TCZ, and proposes a protocol that can reduce complications in patients with TAK undergoing invasive cardiovascular treatment.

Background: Mavacamten, a cardiac myosin inhibitor, significantly improved symptoms and cardiac function vs. placebo in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) in EXPLORER-HCM. However, the efficacy and safety profiles of mavacamten in Japanese patients are unclear.

Methods and Results: HORIZON-HCM is a Phase 3 single-arm study in Japanese patients with symptomatic obstructive HCM. The mavacamten starting dose was 2.5 mg; individualized dose titration occurred in Weeks 6–20 based on Valsalva left ventricular outflow tract (LVOT) gradient and resting left ventricular ejection fraction (LVEF). Overall, 38 patients were treated; 36 completed the 30-week primary treatment analysis period. Clinically significant improvements in postexercise LVOT gradient were observed after 30 weeks of treatment (mean change from baseline −60.7 mmHg). Improvements in N-terminal pro B-type natriuretic peptide, New York Heart Association class, and Kansas City Cardiomyopathy Questionnaire-23 Clinical Summary Score were observed over 30 weeks, and mean LVEF was ≥74% at all visits. Treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 63.2% and 7.9% of patients, respectively; none resulted in treatment discontinuation. One patient experienced a transient asymptomatic reduction in LVEF to <50%. No deaths occurred during the study.

Conclusions: In Japanese patients with obstructive HCM, mavacamten was associated with similar improvements in LVOT gradients, cardiac biomarkers, and symptoms to those observed in EXPLORER-HCM. Treatment was well tolerated with no new safety concerns.

Background: Although the relative apical sparing (RAPS) pattern of left ventricular (LV) longitudinal strain is a hallmark of cardiac amyloidosis, recent studies have raised concerns about its accuracy. The aim of this systematic review was to investigate diagnostic test accuracy (DTA) and prognostic impact of RAPS in cardiac amyloidosis.

Methods and Results: We searched PubMed, Embase, and Scopus for manuscripts that could potentially be used in the DTA arm and prognosis arm. Thirty-seven studies were used for DTA analysis. The pooled sensitivity, specificity, and diagnostic odds ratio were 61% (95% confidence interval [CI] 54–68%), 83% (95% CI 80–86%), and 8.9 (95% CI 6.1–13.1), respectively. These values did not differ regardless of the presence of aortic stenosis, but the diagnostic odds ratio differed significantly among analytical software packages. For the prognosis arm, 6 studies were dichotomously assessed for RAPS, and 5 were assessed quantitatively. The pooled proportion of RAPS was 49% and the pooled estimate of the RAPS ratio was 1.40. Although RAPS was associated with outcome (hazard ratio [HR] 1.87; 95% CI 1.15–3.04; P=0.011), its significance disappeared after trim and fill analysis (HR 1.42; 95% CI 0.85–2.38; P=0.184).

Conclusions: RAPS has a modest DTA with a significant vendor dependency and does not provide robust prognostic information.

Background: The effects of myocarditis after mRNA COVID-19 vaccination (mCV) on myocardial tissue, and the association between cardiomyocyte injury and clinical presentation, are not fully understood.

Methods and Results: We retrospectively registered patients clinically diagnosed with myocarditis after the first or second mCV who underwent endomyocardial biopsy or autopsy from 42 participating centers in Japan. We investigated the histological features and their association with clinical presentation based on cardiomyocyte injury. Forty patients who underwent endomyocardial biopsy were included in the study. Of these, 19 (47.5%) showed mild lymphocytic infiltration and interstitial edema without cardiomyocyte injury. The remaining 21 (52.5%) patients showed cardiomyocyte injury accompanied by infiltrating inflammatory cells: 11 with lymphocytic infiltration, 7 with eosinophilic infiltration, and 3 with myocarditis with both lymphocyte and eosinophil infiltration. Compared with patients without cardiomyocyte injury, those with cardiomyocyte injury were clinically characterized by older age, a balanced sex distribution, less frequent chest pain, and a lower left ventricular ejection fraction. Fifteen of 21 (71.4%) patients with cardiomyocyte injury developed fulminant myocarditis, with 13 (86.7%) requiring mechanical circulatory support; in contrast, none of those without cardiomyocyte injury developed fulminant myocarditis (P<0.001).

Conclusions: Our histological examination of patients with myocarditis after mCV revealed varying degrees of cardiomyocyte injury, ranging from pronounced to absent, along with various types of myocarditis. Cardiomyocyte injury was strongly associated with the severity of myocarditis.

Background: Anticoagulation therapy for atrial fibrillation (AF) has undergone major changes following the introduction of direct oral anticoagulants (DOAC) in 2011. However, the transition of anticoagulation therapy for AF patients with severe renal dysfunction remains to be elucidated.

Methods and Results: Follow-up data, including creatinine clearance (CrCl), were available for 3,706 patients in the Fushimi AF Registry. We divided patients into 3 groups based on CrCl as follows: (1) CrCl ≥50 mL/min; (2) 50 mL/min>CrCl≥30 mL/min; and (3) CrCl <30 mL/min. In patients with CrCl ≥50 mL/min and 50>CrCl≥30 mL/min, prescription of oral anticoagulants increased year-by-year from 2011 to 2021 with a growing proportion of DOAC; however, the prescription of oral anticoagulants remained almost unchanged in those with CrCl <30 mL/min. In patients with CrCl ≥50 mL/min and 50 mL/min>CrCl≥30 mL/min, the incidence of adverse events, including stroke/systemic embolism and major bleeding, was lower among patients enrolled after 2014 than before 2013. However, these trends were not seen in patients with CrCl <30 mL/min.

Conclusions: Despite the increased use of DOAC in patients with AF since 2011, anticoagulation therapy for AF patients with severe renal dysfunction has largely remained unchanged, and a reduction in adverse events in those patients has not been observed.

Background: Guideline-directed medical therapy has become an important component of heart failure (HF) therapy, with sacubitril/valsartan as one of the recommended drugs; however, the real-world prognostic implications of sacubitril/valsartan uptitration are unclear.

Methods and Results: Patients with HF newly initiated on sacubitril/valsartan were registered in a retrospective multicenter study (REVIEW-HF). In all, 995 patients were divided into 3 groups according to the maximum dose achieved: high dose, sacubitril/valsartan 400 mg; intermediate dose, sacubitril/valsartan 200–<400 mg; and low dose, sacubitril/valsartan <200 mg. A total of 397 (39.9%) patients received high-dose sacubitril/valsartan; they had a significantly lower risk of mortality or HF hospitalization than patients in the low-dose (hazard ratio [HR] 0.39; 95% confidence interval [CI] 0.29–0.53; P<0.001) and intermediate-dose (HR 0.64; 95% CI 0.45–0.94; P=0.03) groups. In the multivariable Cox regression model, higher systolic blood pressure and maintained geriatric nutritional risk index were significantly associated with a higher incidence of achieving a high dose of sacubitril/valsartan. Patients who did not receive high-dose sacubitril/valsartan experienced more hypotension during the follow-up period, whereas hyperkalemia, severe renal events, and angioedema did not differ across the achieved dose classifications.

Conclusions: Patients who achieved sacubitril/valsartan uptitration had a better prognosis than those who did not. Before sacubitril/valsartan uptitration, patients need to monitor blood pressure closely to prevent worsening events.

Background: This study analyzed the risk factors for type 1a endoleak after hybrid thoracic endovascular repair (TEVAR) for aortic arch diseases based on preoperative patient characteristics and multidetector computed tomography measurements.

Methods and Results: In all, 213 patients who underwent proximal landing zone 1 and 2 hybrid TEVAR for aortic arch pathologies (zone 1, n=82 [38.5%]; zone 2, n=131 [61.5%]; median age 72 years) between May 2008 and February 2020 were enrolled in this study; the median follow-up period was 6.0 years. The rates of type 1a endoleak at 1, 3, 5, and 10 years were 1.4%, 1.4%, 4.1%, and 4.1%, respectively. Multivariate Cox proportional hazard regression analysis revealed that the angle of the aortic arch was a significant risk factor for type 1a endoleak (hazard ratio 1.08; 95% confidence interval 0.85–0.99; P=0.045). The estimated area under the curve in receiver operating characteristic curve analysis was 0.76, and the cut-off value of the aortic arch angle was 95°.

Conclusions: It is essential to prevent type 1a endoleak, the most severe complication of hybrid TEVAR. The risk factor for type 1a endoleak in this study was a sharper angle of the aortic arch (≤95°). For patients at high risk of type 1a endoleak, it is necessary to consider alternative procedures depending on a patient’s surgical risk.

Background: Our study investigated the prognostic impacts of the interval between collapse and the initiation of cardiopulmonary resuscitation (CPR), and subsequent intervals to defibrillation or epinephrine administration, on 30-day favorable neurological outcomes following out-of-hospital cardiac arrest (OHCA).

Methods and Results: This nationwide population-based cohort study used the All Japan Utstein Registry, encompassing OHCA patients in Japan between January 2006 and December 2021. The primary outcome was 30-day favorable neurological outcomes, defined as Cerebral Performance Category 1 or 2. Three-dimensional plots and multivariable logistic regression models were used to assess the time-dependent prognostic impacts of prehospital CPR interventions. In all, 184,731 OHCA patients (86,246 with shockable rhythm and 98,485 with non-shockable rhythm) were included in the study. Three-dimensional plots revealed that the interval between collapse and initiation of CPR, and subsequent intervals to defibrillation or epinephrine, were independently associated with 30-day favorable neurological outcomes in the groups with shockable and non-shockable rhythms, respectively (P<0.05 for all).

Conclusions: Among patients with witnessed OHCA, there was a dose-response relationship between delays in the collapse-CPR initiation interval, and subsequent intervals to defibrillation or epinephrine administration, and 30-day favorable neurological outcomes. Our findings provide valuable insights into OHCA management.

Background: White blood cell (WBC) counts were reported to be a risk factor for acute adverse events in patients with venous thromboembolism (VTE). However, there are limited data on VTE patients without active cancer.

Methods and Results: The COMMAND VTE Registry-2 was a multicenter study enrolling 5,197 consecutive patients with acute symptomatic VTE. We divided 3,668 patients without active cancer into 4 groups based on WBC count quartiles (Q1–Q4) at diagnosis: Q1, ≤5,899 cells/μL; Q2, 5,900–7,599 cells/μL, Q3, 7,600–9,829 cells/μL; and Q4, ≥9,830 cells/μL. Patients in Q4 more often presented with pulmonary embolism (PE) than patients in Q1, Q2, and Q3 (68% vs. 37%, 53%, and 61%, respectively; P<0.001). The proportion of massive PEs among all PEs was higher in Q4 than in Q1, Q2, and Q3 (21% vs. 3.4%, 5.8%, and 11%, respectively; P<0.001). Compared with Q1, Q2, and Q3, patients in Q4 had a higher cumulative 5-year incidence of all-cause death (17.0%, 15.2%, 16.1%, and 22.8%, respectively; P<0.001) and major bleeding (10.9%, 11.0%, 10.3%, and 14.4%, respectively; P=0.002). The higher mortality risk of Q4 relative to Q2 was consistent regardless of the presentations of VTEs.

Conclusions: An elevated WBC count on VTE diagnosis was associated with a higher risk of mortality and major bleeding regardless of VTE presentation, suggesting the potential usefulness of WBC counts for further risk stratification.

Background: An acute hyperglycemic status is reportedly associated with poor prognosis in patients with acute cardiovascular diseases. Although the stress hyperglycemia ratio (SHR) is used to evaluate the hyperglycemic condition on admission, relationships between SHR and clinical outcomes, particularly heart failure (HF), remain uncertain in acute myocardial infarction (AMI).

Methods and Results: This retrospective multicenter study included 2,386 patients with AMI undergoing percutaneous coronary intervention. SHR was calculated using blood glucose and HbA1c levels. Co-primary endpoints included HF-related events (death, worsening HF, and hospitalization for HF) and major adverse cardiovascular events (MACE; death, recurrent AMI, and ischemic stroke) during the index hospitalization and after discharge. The mean (±SD) SHR was 1.30±0.51; HF events and MACE occurred in 680 (28.5%) and 233 (9.8%) patients during hospitalization, respectively. SHR was independently associated with in-hospital HF events and MACE. Of 2,017 patients who survived to discharge, 195 (9.7%) and 214 (10.6%) experienced HF events and MACE, respectively, over a median follow-up of 536 days. The risk of HF events was higher in patients with a high (>1.45) SHR than in those with SHR ≤1.45; there was no significant difference in MACE rates after discharge between these 2 groups.

Conclusions: In AMI patients, SHR was predictive of in-hospital outcomes, including HF events and MACE, whereas after discharge a higher SHR was associated with higher HF risks, but not MACE.

Background: Elevated lipoprotein(a) [Lp(a)] levels are a causal risk factor for peripheral artery disease. However, data on their effect on delayed wound healing in patients with chronic limb-threatening ischemia (CLTI) are limited. The present study assessed the association between elevated Lp(a) levels and delayed wound healing in patients with CLTI.

Methods and Results: This study included 280 patients who successfully received endovascular therapy for CLTI between September 2016 and August 2021. High Lp(a) levels were defined as those >30 mg/dL. The primary outcome was wound healing. During a median follow-up of 20.4 months (interquartile range 6.8–38.6 months), 146 patients achieved wound healing. The wound healing rate at 24 months was significantly lower in the high Lp(a) than low Lp(a) group (41.1% vs. 86.3%, respectively; P<0.001). The adjusted risk ratio was 0.19 (95% confidence interval 0.13–0.29, P<0.001). Lp(a) levels of 31–50 and >50 mg/dL, but not 16–30 mg/dL, were significantly associated with delayed wound healing relative to Lp(a) levels of ≤15 mg/dL.

Conclusions: Elevated Lp(a) levels were independently associated with delayed wound healing in patients with CLTI treated with endovascular therapy.

Background: The optimal duration of dual antiplatelet therapy (DAPT) in patients with chronic kidney disease undergoing percutaneous coronary intervention (PCI), especially with third-generation drug-eluting stents (DES), remains unknown.

Methods and Results: We conducted a prespecified post hoc analysis of the HOST-IDEA trial, randomizing patients undergoing PCI with third-generation DES to 3- to 6-month or 12-month DAPT. In all, 1,997 patients were grouped by their estimated glomerular filtration rate (eGFR): high (>90 mL/min/1.73 m²), intermediate (60–90 mL/min/1.73 m²), and low (<60 mL/min/1.73 m²). The primary outcome was net adverse clinical events (NACE), a composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization, stent thrombosis, or major bleeding (Bleeding Academic Research Consortium Type 3 or 5) at 12 months. Secondary outcomes were target lesion failure (TLF) and major bleeding. The low eGFR group had the highest rates of NACE, TLF, and major bleeding compared with the other 2 groups (P<0.001). Rates of NACE were similar in the 3- to 6-month and 12-month DAPT in the high (2.9% vs. 3.2%; P=0.84), intermediate (2.1% vs. 2.8%, P=0.51), and low (8.9% vs. 9.1%; hazard ratio 0.99; P=0.97; P_interaction=0.88) eGFR groups. TLF and major bleeding events showed similar trends.

Conclusions: In patients undergoing PCI with third-generation DES, 3- to 6-month DAPT was comparable to 12-month DAPT for clinical outcomes regardless of renal function.

Background: Although the efficacy of an implantable cardioverter defibrillator (ICD) in preventing sudden cardiac death is well established, the incidence and predictors of appropriate ICD therapy in Japanese ischemic heart disease (IHD) patients remain unclear.

Methods and Results: We retrospectively studied Japanese 141 IHD patients undergoing transvenous ICD or cardiac resynchronization therapy with a defibrillator (CRT-D) implantation for primary or secondary prevention at Hirosaki University Hospital. Over a mean (±SD) follow-up period of 5.5±2.8 years, the incidence of appropriate ICD therapy was similar in the primary and secondary prevention groups, although it was relatively more frequent in the first 2 years in the secondary prevention group. Four patients died due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF), mainly due to post-shock pulseless electrical activity. Once patients had received their first appropriate ICD therapy, 49.2% received second appropriate ICD therapy within 6 months. Cox proportional hazard analysis revealed that sustained VT as an index life-threatening ventricular tachyarrhythmia before ICD/CRT-D implantation was an independent predictor of appropriate ICD therapy, but VF was not.

Conclusions: The incidence of appropriate ICD therapy was comparable in primary and secondary prevention among Japanese IHD patients. We need to recognize the high-risk period for second appropriate ICD therapy after the first therapy and sustained VT as index life-threatening ventricular tachyarrhythmia as a risk factor for appropriate ICD therapy.

Background: Few studies have investigated the clinical characteristics and in-hospital outcomes of patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) using real-world databases in the coronary intervention era.

Methods and Results: We conducted a retrospective analysis of 22,236 patients (mean [±SD] age 68±13 years, 23.4% female) enrolled in the Japan Acute Myocardial Infarction Registry (JAMIR) between 2011 and 2016. Based on urgent coronary angiography findings, 286 (1.3%) patients were diagnosed as MINOCA, and the remaining 21,950 (98.7%) as MI with obstructive coronary artery disease (MI-CAD). MINOCA patients were characterized by younger age, fewer coronary risk factors, lower rate of ST-elevation myocardial infarction, lower Killip classification, and lower peak creatinine phosphokinase levels than MI-CAD patients. In-hospital all-cause mortality did not differ between the MINOCA and MI-CAD groups (5.2% vs. 5.7%, respectively; P=0.82). Comparing cause-specific mortality, non-cardiac mortality was higher in the MINOCA than MI-CAD group (4.2% vs. 1.6%; P<0.01). Importantly, non-cardiac death was more prevalent among elderly (≥65 years) than younger (<65 years) patients in the MI-CAD group, whereas this trend was not observed in the MINOCA group.

Conclusions: Analysis of the real-world JAMIR database revealed a relatively high prevalence of non-cardiac death among MINOCA patients, underscoring the need for comprehensive management to improve disease prognosis, particularly in younger patients.

Background: Mitochondrial dysfunction in the heart is associated with the development of heart failure (HF). However, the clinical consequences of mitochondrial structural abnormalities in patients with HF remain unexplored.

Methods and Results: Ninety-one patients with left ventricular (LV) systolic dysfunction who underwent endomyocardial biopsy (EMB) were enrolled in the study. Myocardial specimens were obtained from the right ventricular septum. Specimens were characterized using electron microscopy to assess mitochondrial size, outer membrane disruption, and cristae disorganization. The primary endpoint was a composite of cardiovascular death and unplanned hospitalization for HF. Patients were classified into LV reverse remodeling (LVRR)-positive (n=52; 57.1%) and LVRR-negative (n=39; 42.9%) groups. Cristae disorganization was observed in 21 (23.1%) patients: 6 (11.5%) in the LVRR-positive group and 15 (38.5%) in the LVRR-negative group (P=0.005). During the 1-year post-EMB observation period, 16 patients (17.6%) met the primary endpoint, with 2 (2.2%) cardiovascular deaths and 14 (15.4%) HF hospitalizations. Cristae disorganization (P=0.002) was significantly associated with the endpoints, independent of age (P=0.115), systolic blood pressure (P=0.004), B-type natriuretic peptide level (P=0.042), and mitral regurgitation (P=0.003).

Conclusions: We classified mitochondrial structural abnormalities and showed that cristae disorganization was associated with LVRR and worse prognosis. These findings may affect the management of patients with HF and systolic dysfunction who undergo EMB.

Background: High-sensitivity cardiac troponin T (hs-cTnT) was proposed as a simple and useful diagnostic tool for cardiac amyloidosis (CA). We performed exploratory systemic screening using hs-cTnT to detect wild-type transthyretin CA (ATTRwt-CA) in outpatient and community-based settings.

Methods and Results: This study was a prospective multicenter study including 8 internal medicine clinics in Kochi Prefecture, Japan. Consecutive individuals aged ≥70 years who visited those clinics as outpatients were enrolled. Patients with a prior diagnosis of CA or a history of heart failure hospitalization were excluded. We measured hs-cTnT levels in the enrolled individuals at each clinic, and those with elevated hs-cTnT levels (≥0.03ng/mL) received further detailed examination, including remeasurement of hs-cTnT. The diagnosis of ATTRwt-CA was confirmed by biopsy-proven transthyretin. Of 1,141 individuals enrolled in the study, 55 (4.8%) had elevated hs-cTnT levels. Of the 33 patients who underwent further examination, 22 had elevated hs-cTnT levels at remeasurement. Finally, 2 men were diagnosed with ATTRwt-CA. The prevalence of ATTRwt-CA was 9.1% (2/22) among patients with elevated hs-cTnT levels at two examinations, and at least 0.18% (2/1,141) in the whole study population.

Conclusions: Measurement of hs-cTnT will help to screen for patients with undiagnosed ATTRwt-CA in primary care practice.

Background: The short-term mortality associated with veno-arterial extracorporeal membrane oxygenation combined with the Impella device (termed ECPELLA) for acute myocardial infarction complicated by cardiogenic shock (AMI-CS) remains unclear.

Methods and Results: The Japanese Registry for Percutaneous Ventricular Assist Devices (J-PVAD) includes data on all patients treated with an Impella in Japan. We extracted data for 922 AMI-CS patients who underwent ECPELLA support and conducted an exploratory analysis focusing on 30-day mortality. The median age of patients was 69 years, and 83.8% were male. The overall 30-day mortality was 46.1%. Factors associated with mortality included age >80 years, in-hospital cardiac arrest, systolic blood pressure <90 mmHg, serum creatinine >1.5 mg/dL, and serum lactate >4.0 mmol/L. In patients aged >80 years with any of these factors, mortality was significantly higher than in those without, ranging from 57.5% to 64.9%. The J-PVAD score assigns 1 point per predictor, with a C-statistic of 0.620 (95% confidence interval 0.586–0.654). The 30-day mortality was 20.0% for a J-PVAD score of 0, increasing to 70.0% for a score of 5.

Conclusions: The J-PVAD data indicate high short-term mortality in AMI-CS patients treated with ECPELLA, particularly among older patients. Further studies are needed to validate this risk stratification in this patient subset.

Background: Implantable cardioverter defibrillators (ICDs) reduce mortality associated with ventricular arrhythmia in high-risk patients with cardiovascular disease. Machine learning (ML) approaches are promising tools in arrhythmia research; however, their application in predicting ventricular arrhythmias in patients with ICDs remains unexplored. We aimed to predict and stratify ventricular arrhythmias requiring ICD therapy using 12-lead electrocardiograms (ECGs) in patients with an ICD.

Methods and Results: This retrospective analysis included 200 adult patients who underwent ICD implantation at a single center. Patient demographics, clinical features, and 12-lead ECG data were collected. Unsupervised learning techniques, including K-means and hierarchical clustering, were used to stratify patients based on 12-lead ECG features. Dimensionality reduction methods were also used to optimize clustering accuracy. The silhouette coefficient was used to determine the optimal method and number of clusters. Of the 200 patients, 59 (29.5%) received appropriate therapy. The mean age of patients was 62.3 years, and 81.0% were male. The mean follow-up period was 2,953 days, with no significant intergroup differences. Hierarchical clustering into 3 clusters proved to be the most accurate (silhouette coefficient=0.585). Kaplan-Meier curves for these 3 clusters revealed significant differences (P=0.026).

Conclusions: We highlight the potential of ML-based clustering using 12-lead ECGs to help in the risk stratification of ventricular arrhythmia. Future research in a larger multicenter setting may provide further insights and refine ICD indications.

Background: Persistent atrial fibrillation (AF) patients with tachycardia-induced cardiomyopathy (TIC) undergoing catheter ablation have similar or even better outcomes than patients without TIC. Data regarding atrial substrate remodeling are scarce in cases of TIC. We assessed regional distribution of left atrial (LA) bipolar voltage, the extent of low-voltage zones (LVZs), and outcomes of voltage-guided ablation in AF patients with and without TIC.

Methods and Results: In all, 139 patients with persistent AF presenting for a first voltage-guided catheter ablation were enrolled, 61 with TIC and 78 with structurally normal hearts. LA voltage maps were obtained using a 3-dimensional electroanatomical mapping system in sinus rhythm. LVZ was defined as <0.5 mV. Compared with non-TIC patients, TIC patients had a lower indexed LA volume (median [interquartile range] 58.6 [50.6–68.7] vs. 63.4 [60.1–76.1] mL/m²; P<0.01) and higher LA voltage (2.3 [1.5–2.8] vs. 1.7 [1–2.6] mV; P=0.02). LVZs were less frequently found in patients with than without TIC (8 [13.1%] vs. 30 [39%]; P<0.01). There was no significant difference in atrial tachyarrhythmia (AT)-free survival rate over a 36-month follow-up between the 2 groups (log-rank test, P=0.176). No predictor of AT recurrence was identified.

Conclusions: TIC patients exhibit less LA substrate remodeling with a smaller LA volume, higher bipolar voltage, and fewer LVZs than non-TIC patients. They have a similar favorable outcome after a single procedure.

Background: Exercise capacity is related to mortality and morbidity in heart failure (HF) patients. Determinants of exercise capacity in transthyretin cardiac amyloidosis (ATTR-CA) have not been established.

Methods and Results: This single-center study retrospectively evaluated ATTR-CA patients and patients with non-amyloidosis HF with preserved/mildly reduced ejection fraction (HFpEF/HFmrEF) (n=32 and n=51, respectively). In the ATTR-CA group, the median age was 75.5 years (interquartile range [IQR] 71.3–78.8 years), 90.6% were male, and the median left ventricular (LV) ejection fraction was 53.5% (IQR 41.4–65.6%). Cardiopulmonary exercise tests revealed a median peak oxygen consumption and anaerobic threshold of 15.9 (IQR 11.6–17.4) and 10.6 (IQR 8.5–12.0] mL/min/kg, respectively, and ventilatory efficiency (minute ventilation/carbon dioxide production [V̇_E/V̇_CO2] slope) of 35.5 (IQR 32.0–42.5). Among exercise variables, V̇_E/V̇_CO2slope has the greatest prognostic value. Univariate analysis revealed a significant correlation between V̇_E/V̇_CO2slope and age, LV global longitudinal strain, tricuspid annular plain systolic excursion/pulmonary arterial systolic pressure (TAPSE/PASP) ratio, and mixed venous oxygen saturation. In multivariate analyses, the TAPSE/PASP ratio was an independent predictor of V̇_E/V̇_CO2slope (95% confidence interval −44.5, −10.8; P=0.0067). In non-amyloidosis HFpEF/HFmrEF patients, the TAPSE/PASP ratio was not independently correlated with V̇_E/V̇_CO2slope.

Conclusions: Right ventricular–pulmonary artery coupling estimated by the TAPSE/PASP ratio determines exercise capacity in ATTR-CA patients. This highlights the importance of early therapeutic intervention against underappreciated right ventricular dysfunction associated with ATTR-CA.

Background: The ONCO DVT study demonstrated potential benefits of extended edoxaban treatment in patients with isolated distal deep vein thrombosis in terms of thrombotic risk. However, the risk-benefit balance in patients with anemia remains unclear.

Methods and Results: This prespecified subgroup analysis included 601 patients, divided into anemia (n=402) and no-anemia (n=199) groups. The primary endpoint was symptomatic recurrent venous thromboembolism (VTE) or VTE-related death. Anemia was defined as hemoglobin <12 g/dL for women and <13 g/dL for men. In the anemia subgroup, the primary endpoint occurred in 3 (1.5%) and 17 (8.4%) patients in the 12- and 3-month edoxaban treatment groups, respectively (odds ratio [OR] 0.17; 95% confidence interval [CI] 0.05–0.58), compared with 0 and 5 (4.9%) patients, respectively, in the no-anemia subgroup (P interaction=0.997). Major bleeding occurred in 26 (13.1%) and 17 (8.4%) patients with anemia in the 12- and 3-month edoxaban treatment groups, respectively (OR 1.64; 95% CI 0.86–3.14), compared with 2 (2.1%) and 5 (4.9%) patients without anemia (OR 0.67; 95% CI 0.26–1.73; P interaction=0.13).

Conclusions: Regardless of the presence of anemia, edoxaban treatment for 12 months was superior to treatment for 3 months in reducing thrombotic events, whereas the risk of major bleeding did not differ significantly between the 2 treatment groups.

Background: This study aimed to clarify recent clinical features and treatment outcomes in Japanese patients with newly diagnosed Takayasu arteritis (TAK) during the first 2 years of treatment.

Methods and Results: A nationwide multicenter retrospective cohort study for TAK was implemented to collect data between 2007 and 2014. The primary outcome of the study was clinical remission at Week 24. Of the 184 participants registered, 129 patients with newly diagnosed TAK were analyzed: 84% were female and the mean age at onset was 35 years. Clinical symptoms at diagnosis were mostly associated with large-vessel lesions. Frequent sites of vascular involvement included the carotid artery, subclavian artery, aortic arch, and descending aorta. The mean initial dose of prednisolone administered was 0.68 mg/kg/day, and 59% and 17% of patients received immunosuppressive drugs and biologics, respectively, by Week 104. Clinical remission at Week 24 and sustained clinical remission with daily prednisolone at ≤10 mg at Week 52 were achieved in 107 (82.9%) and 51 (39.5%) patients, respectively. The presence of signs and symptoms linked to large-vessel lesions was associated with failure to achieve sustained clinical remission at Week 52.

Conclusions: We elucidated the clinical characteristics, treatment outcomes, and factors associated with failure to achieve sustained clinical remission in patients with newly diagnosed TAK in Japan during the first 2 years of treatment.

Background: The number of older people in Japan is increasing more quickly than in other countries; with this aging of society, the number of elderly patients hospitalized for acute heart failure (HF) is also increasing. The treatment and prognosis of acute HF may be changing, but there are insufficient recent data, especially for octogenarian and older patients.

Methods and Results: This study investigated the characteristics and treatment of acute HF patients in Japan. From 2018 to 2020, 1,146 patients from 7 Tokai area hospitals were followed for at least 1 year. The mean age was 78 years. Compared with patients aged <80 years, those aged ≥80 years were more likely to be female (57.4% vs. 34.2%), have a lower body mass index (22.2 vs. 24.9 kg/m²), and have HF with preserved ejection fraction (43.1% vs. 21.4%), and less likely to have HF with reduced ejection fraction (38.9% vs. 61.7%). During hospitalization, 6.5% died. After discharge, patients faced high risks of rehospitalization for HF and death (27.6 and 14.2 per 100 patient-years, respectively). Notably, prescription rates of HF medications have declined over time for all patients, but especially for those aged ≥80 years.

Conclusions: Guideline-directed medical therapy should be provided based on a thorough understanding of an individual’s background rather than withheld simply because of clinical inertia due to a patient’s advanced age.

Background: Cardiac sarcoidosis (CS) may result in systolic heart failure (heart failure with reduced ejection fraction [HFrEF]), but its response to guideline-directed medical therapy (GDMT) remains uncertain.

Methods and Results: We investigated 881 patients evaluated for CS to identify those with diagnosed CS, left ventricular ejection fraction (LVEF) ≤40% at diagnosis, and follow-up echocardiogram within 11–24 months. Demographics, LVEF, GDMT as quantified by Kansas City Medical Optimization (KCMO) score, and immunosuppressive treatment were recorded. The primary outcome was a composite of event-free survival (unplanned heart failure hospitalization, left ventricular assist device [LVAD]/heart transplant, or death). Seventy-nine (9%) CS patients met the inclusion criteria (35% female, median age 57 years, mean LVEF 30.9%, median New York Heart Association class II [46%], mean number of GDMT agents 1.7, and mean KCMO score 31.8). Most (87%) were treated with immunosuppressive treatment. At follow-up (median 16 months), the mean number of GDMT agents increased to 2.2 (P=0.02), and the mean KCMO score to 70.1 (P<0.001). Mean LVEF improved to 39.9% (excluding LVAD/transplant; P<0.001) and the change in LVEF was correlated with follow-up KCMO score (P<0.001). The primary outcome occurred in 13 (16%) patients and differed by KCMO score (log-rank P<0.001), but not by immunosuppressive treatment (log-rank P=0.36).

Conclusions: GDMT optimization is associated with better cardiac remodeling and clinical outcomes in CS patients with HFrEF.

Background: Anemia, a common comorbidity in older patients with heart failure (HF) and atrial fibrillation (AF), is associated with an increased risk of adverse events. This study evaluated the prognostic effects of longitudinal changes in anemia status on clinical outcomes in patients with AF.

Methods and Results: We prospectively evaluated data of 1,388 patients with AF from the Hokuriku-Plus AF Registry (1,010 men; mean [±SD] age 72.3±9.7 years) and recorded the incidence of death, HF, thromboembolism, and major bleeding. Of these patients, the 1,233 for whom hemoglobin levels were available at baseline and at the 1-year follow-up were further evaluated. Patients were categorized into 3 groups based on longitudinal changes in 1-year anemia status: Group 1, AF without anemia; Group 2, AF with improved anemia; and Group 3, AF with sustained or new-onset anemia. Over the 1–5 years of follow up, the incidences of death, HF, thromboembolism, and major bleeding were significantly higher among patients with than without anemia. In addition, the incidence of death or HF was significantly higher in Group 3 than in Groups 1 and 2. Multivariate analysis revealed no anemia or improvement in anemia in 1 year as an independent predictor for a favorable prognosis for cardiovascular death and HF.

Conclusions: Recovery from anemia may be associated with a favorable clinical course of AF.

Background: Possible etiologies of out-of-hospital cardiac arrest (OHCA), including aortic dissection, ruptured aortic aneurysms, and pulmonary embolism, may be classified as non-cardiac causes. We investigated whether cardiac and non-cardiac OHCAs increased following the Kumamoto earthquake and whether the impact on OHCAs extended to regions far from the epicenter.

Methods and Results: We prospectively analyzed a nationwide registry of patients who experienced OHCAs between January 2013 and December 2019. Data from cases registered in 7 prefectures, including Kumamoto (Kyushu region; n=82,060), in the All-Japan Utstein Registry were analyzed for OHCAs of cardiac and non-cardiac origin. The numbers of OHCAs before and after the Kumamoto earthquake were compared using an interrupted time series analysis. The incidence of both cardiac (rate ratio [RR] 1.22) and non-cardiac (RR 1.27) OHCAs in Kumamoto Prefecture increased after the earthquake. The difference disappeared when the analysis was limited to patients with non-cardiac OHCAs with a clear cause of cardiac arrest. The number of cardiac and non-cardiac OHCAs did not increase in other prefectures within the Kyushu region.

Conclusions: The Kumamoto earthquake led to an increase in the incidence of cardiac and non-cardiac OHCAs. However, this was attenuated by increasing distance from the epicenter. Except for cardiac causes, cases complicated by earthquake-related events may include non-cardiac OHCAs due to vascular diseases that might be overlooked.

Background: Heart failure (HF) patients with complex care needs often experience exacerbations during the transitional phase as care providers and settings change. Regional collaboration aims to ensure continuity of care; however, its impact on vulnerable patients certified as needing support or care under the Japanese long-term care insurance (LTCI) system remains unclear.

Methods and Results: We implemented a regional collaborative program for HF patients involving 3 pillars of transitional care with general practitioners and nursing care facilities: (1) standardized health monitoring using a patient diary and identification of exacerbation warning signs; (2) standardized information sharing among care providers; and (3) standardized HF management manuals. We evaluated outcomes within 1 year of discharge for patients hospitalized with HF and referred to other facilities for outpatient follow-up in 2017–2018 before program implementation (n=110) and in 2019–2020 after implementation (n=126). Patients with LTCI frequently received non-cardiologist follow up and care services and had a higher risk of all-cause mortality and HF readmission compared with those without LTCI (P<0.05). Program implementation was significantly associated with a greater reduction in HF readmissions among patients with LTCI compared with those without (P<0.05 for interaction), although mortality rates remained unchanged.

Conclusions: A regional collaborative program significantly reduces HF readmissions in HF patients with LTCI who are at high risk of worsening HF.

Background: This study evaluated right ventricular (RV) volume, strain, and morphology using cardiac 4-dimensional computed tomography (4D-CT) to detect pulmonary hypertension (PH) in adults with repaired tetralogy of Fallot (TOF) scheduled for transcatheter pulmonary valve implantation (TPVI).

Methods and Results: Using cardiac 4D-CT data, we calculated RV strain in 3 different geometries and RV outflow tract (RVOT) mass in 42 patients with repaired TOF. We compared RV strain and RVOT mass between patients with and without PH. Receiver operating characteristic (ROC) analysis was conducted to evaluate the diagnostic performance of these measurements for identifying PH. Four-chamber (4ch) strain was significantly smaller for patients with (n=10) than without (n=32) PH (8.8±1.7% vs. 11.1±2.4%, respectively; P<0.01), whereas RVOT mass was significantly larger in the PH group (12.5±3.5 vs. 9.2±3.2 cm²; P<0.01). ROC analysis of the diagnostic performance revealed that the respective sensitivity and specificity was 70% and 84% (area under the curve [AUC]=0.784) for 4ch strain of 8.8%; 80% and 69% (AUC=0.766) for RVOT mass of 10.7 cm²; and 80% and 81% (AUC=0.844) for a 4ch strain/RVOT mass ratio of 0.97.

Conclusions: RVOT mass and 4ch strain obtained from cardiac 4D-CT may be helpful for identifying PH in patients with repaired TOF.

Background: Electrical storms (E-storms), defined as multiple fatal ventricular arrhythmias over a short period, negatively affect the prognosis of patients receiving an implantable cardioverter defibrillator or cardiac resynchronization therapy with a defibrillator (ICD/CRT-D). However, the prognostic impact of recurrent E-storms has not been well elucidated.

Methods and Results: We analyzed the association between E-storm recurrences and mortality using data from 1,274 participants in the Nippon Storm Study, a prospective observational study conducted at 48 ICD/CRT-D centers in Japan. Differences in E-storm recurrences by patient characteristics were evaluated using the mean cumulative function (MCF), which is the cumulative number of E-storm episodes per patient as a function of time. Patients with multiple E-storms had a 3.39-fold higher mortality risk than those without E-storms (95% confidence interval 1.82–6.28; P<0.01). However, there was no significant difference in mortality risk between patients with a single E-storm and those without E-storms. The MCF curve exhibited a slower ascent in patients who received primary prevention ICD/CRT-D than in those who received secondary prevention ICD/CRT-D. However, when analyzing only patients with E-storms, the MCF curves demonstrated comparable trajectories in both groups.

Conclusions: E-storm recurrences may have a negative impact on prognosis. Once patients with primary prevention experience an E-storm episode, they face a similar risk of subsequent recurrent E-storms as patients with secondary prevention.