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Abstract The pathophysiology of variant transthyretin (TTR) amyloidosis (ATTRv) is associated with destabilizing mutations in the TTR tetramer. However, why TTR with a wild-type genetic sequence misfolds and aggregates in wild-type transthyretin amyloidosis (ATTRwt) is unknown. Here, we evaluate kinetic TTR stability with a newly developed ELISA system in combination with urea-induced protein denaturation. Compared with that in control patients, endogenous TTR in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) exhibited thermodynamic instability, indicating that circulating TTR instability may be associated with the pathogenesis of ATTRwt as well as ATTRv. Our findings provide new insight into the underlying mechanisms of ATTRwt.

Abstract There is no treatment for acute aortic dissection (AAD) targeting inflammatory cells. We aimed to identify the new therapeutic targets associated with inflammatory cells. We characterized the specific distribution of myeloid cells of both human type A AAD samples and a murine AAD model generated using angiotensin II (ANGII) and β-aminopropionitrile (BAPN) by single-cell RNA sequencing (scRNA-seq). We also examined the effect of an anti-interleukin-1β (IL-1β) antibody in the murine AAD model. IL1B+ inflammatory macrophages and classical monocytes were increased in human AAD samples. Trajectory analysis demonstrated that IL1B+ inflammatory macrophages differentiated from S100A8/9/12+ classical monocytes uniquely observed in the aorta of AAD. We found increased infiltration of neutrophils and monocytes with the expression of inflammatory cytokines in the aorta and accumulation of inflammatory macrophages before the onset of macroscopic AAD in the murine AAD model. In blocking experiments using an anti-IL-1β antibody, it improved survival of murine AAD model by preventing elastin degradation. We observed the accumulation of inflammatory macrophages expressing IL-1β in both human AAD samples and in a murine AAD model. Anti-IL-1β antibody could improve the mortality rate in mice, suggesting that it may be a treatment option for AAD.

Background Stage B heart failure (HF) refers to structural heart disease without signs or symptoms of HF, so that early intervention may delay or prevent the onset of overt HF. However, stage B HF is a very broad concept, and risk stratification of such patients can be challenging. Methods and Results We conducted a prospective study of data for 1646 consecutive patients with HF from the KUNIUMI (Kobe University Heart Failure Registry in Awaji Medical Center) registry chronic cohort. The definition of HF stages was based on current guidelines for classification of 29 patients as stage A HF, 761 as stage B HF, 827 as stage C HF, and 29 patients as stage D HF. The primary end point was the time‐to‐first‐event defined as cardiovascular death or HF hospitalization within 2.0 years of follow‐up. A maximum of 6 adjustment factor points was assigned based on Cox proportional hazards analysis findings for the hazard ratio (HR) of independent risk factors for the primary end point: 1 point for anemia, estimated glomerular filtration rate 14, and 2 points for clinical frailty scale >3. Patients with stage B HF were stratified into 3 groups, low risk (0–1 points), moderate risk (2–3 points), and high risk (4–6 points). Based on this scoring system (BEEAF2 [brain natriuretic peptide, estimated glomerular filtration rate, ratio of early transmitral flow velocity to early diastolic mitral annular velocity, anemia, and frailty]), the outcome was found to become worse in accordance with risk level. High‐risk patients with stage B HF and patients with stage C HF showed similar outcomes. Conclusions Our scoring system offers an easy‐to‐use evaluation of risk stratification for patients with stage B HF.

Objective: The incidence of postoperative complications, including dysphagia, increases as the population undergoing cardiovascular surgery ages. This study aimed to explore the potential of maximum phonation time (MPT) as a simple tool for predicting postextubation dysphagia (PED) and major adverse cardiac and cerebrovascular events (MACCEs). Methods: This retrospective study included 442 patients who underwent elective cardiac surgery at a university hospital. MPT was measured before surgery, and patients were stratified into 2 groups based on normal and abnormal MPTs. Postoperative complications, including PED and MACCEs, were also investigated. Swallowing status was assessed using the Food Intake Level Scale. Results: MPT predicted PED with prevalence of 11.0% and 18.0% in the normal and abnormal MPT groups, respectively (P = .01). During the follow-up period, MACCEs developed in 17.0% of patients. Frailty, European System for Cardiac Operative Risk Evaluation II score, PED, and MPT were markedly associated with MACCEs (adjusted hazard ratios: 2.25, 1.08, 1.96, and 0.96, respectively). Mediation analysis revealed that MPT positively influenced PED and MACCEs, whereas PED positively influenced MACCEs. The trend in restricted cubic spline analysis indicated that the hazard ratio for MACCEs increased sharply when MPT was

Abstract Stress has garnered significant attention as a prominent risk factor for inflammation-related diseases, particularly cardiovascular diseases (CVDs). However, the precise mechanisms underlying stress-driven CVDs remain elusive, thereby impeding the development of preventive and therapeutic strategies. To explore the correlation between plasma lipid metabolites and human depressive states, liquid chromatography–mass spectrometry (LC/MS) based analysis of plasma and the self-rating depression (SDS) scale questionnaire were employed. We also used a mouse model with restraint stress to study its effects on plasma lipid metabolites and stenotic vascular remodeling following carotid ligation. In vitro functional and mechanistic studies were performed using macrophages, endothelial cells, and neutrophil cells. We revealed a significant association between depressive state and reduced plasma levels of 4-oxoDHA, a specific omega-3 fatty acid metabolite biosynthesized by 5-lipoxygenase (LO), mainly in neutrophils. In mice, restraint stress decreased plasma 4-oxoDHA levels and exacerbated stenotic vascular remodeling, ameliorated by 4-oxoDHA supplementation. 4-oxoDHA enhanced Nrf2-HO-1 pathways, exerting anti-inflammatory effects on endothelial cells and macrophages. One of the stress hormones, noradrenaline, reduced 4-oxoDHA and the degraded 5-LO in neutrophils through the proteasome system, facilitated by dopamine D2-like receptor activation. Our study proposed circulating 4-oxoDHA levels as a stress biomarker and supplementation of 4-oxoDHA as a novel therapeutic approach for controlling stress-related vascular inflammation.

Background Perivascular inflammation contributes to the development of atherosclerosis and microcirculatory dysfunction. Pericoronary adipose tissue (PCAT) attenuation, measured by coronary computed tomography angiography, is a potential indicator of coronary inflammation. However, the relationship between PCAT attenuation, microcirculatory dysfunction, and periprocedural myocardial injury (PMI) remains unclear. Methods and Results Patients with chronic coronary syndrome who underwent coronary computed tomography angiography before percutaneous coronary intervention were retrospectively identified. PCAT attenuation and adverse plaque characteristics were assessed using coronary computed tomography angiography. The extent of microcirculatory dysfunction was evaluated using the angio‐based index of microcirculatory resistance before and after percutaneous coronary intervention. Overall, 125 consecutive patients were included, with 50 experiencing PMI (PMI group) and 75 without PMI (non‐PMI group). Multivariable analysis showed that older age, higher angio‐based index of microcirculatory resistance, presence of adverse plaque characteristics, and higher lesion‐based PCAT attenuation were independently associated with PMI occurrence (odds ratio [OR], 1.07 [95% CI, 1.01–1.13]; P=0.02; OR, 1.06 [95% CI, 1.00–1.12]; P=0.04; OR, 6.62 [95% CI, 2.13–20.6]; P=0.001; and OR, 2.89 [95% CI, 1.63–5.11]; P

Abstract Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare and critical malignancy‐related disease characterized by acute progressive pulmonary hypertension (PH). In most cases of PTTM, the cancer can be diagnosed in advance. Identification of the primary cancer is valuable for PTTM diagnosis. Here, we present the case of a patient with PTTM due to early gastric carcinoma in whom the diagnosis of malignant cancer was not revealed until macroscopic autopsy findings. This case highlights the importance of recognizing causative occult early gastric cancer leading to PTTM in cases of acute progressive PH.

Background Ultraviolet B (UV‐B) irradiation is an effective treatment for human cutaneous disorders and was shown to reduce experimental atherosclerosis by attenuating immunoinflammatory responses. The aim of this study was to clarify the effect of specific wavelengths of UV‐B on atherosclerosis and the underlying mechanisms focusing on immunoinflammatory responses. Methods and Results Based on light‐emitting diode technology, we developed novel devices that can emit 282 nm UV‐B, which we do not receive from natural sunlight, 301 nm UV‐B, and clinically available 312 nm UV‐B. We irradiated 6‐week‐old male atherosclerosis‐prone Apoe−/− (apolipoprotein E‐deficient) mice with specific wavelengths of UV‐B and evaluated atherosclerosis and immunoinflammatory responses by performing histological analysis, flow cytometry, biochemical assays, and liquid chromatography/mass spectrometry‐based lipidomics. Irradiation of 282 nm UV‐B but not 301 or 312 nm UV‐B significantly reduced the development of aortic root atherosclerotic plaques and plaque inflammation. This atheroprotection was associated with specifically augmented immune responses of anti‐inflammatory CD4+ Foxp3 (forkhead box P3)+ regulatory T cells in lymphoid tissues, whereas responses of other immune cells were not substantially affected. Analysis of various lipid mediators revealed that 282 nm UV‐B markedly increased the ratio of proresolving to proinflammatory lipid mediators in the skin. Conclusions We demonstrated that 282 nm UV‐B irradiation effectively reduces aortic inflammation and the development of atherosclerosis by systemically augmenting regulatory T‐cell responses and modulating the balance between proresolving and proinflammatory lipid mediators in the skin. Our findings indicate that a novel 282 nm UV‐B phototherapy could be an attractive approach to treat atherosclerosis.

Abstract High-density lipoprotein (HDL) cholesterol efflux capacity (CEC), which is a conventional metric of HDL function, has been associated with coronary heart disease risk. However, the CEC assay requires cultured cells and takes several days to perform. We previously established a cell-free assay to evaluate cholesterol uptake capacity (CUC) as a novel measure of HDL functionality and demonstrated its utility in coronary risk stratification. To apply this concept clinically, we developed a rapid and sensitive assay system based on a chemiluminescent magnetic particle immunoassay. The system is fully automated, providing high reproducibility. Measurement of CUC in serum is completed within 20 min per sample without HDL isolation, a notably higher throughput than that of the conventional CEC assay. CUC decreased with myeloperoxidase-mediated oxidation of HDL or in the presence of N-ethylmaleimide, an inhibitor of lecithin: cholesterol acyltransferase (LCAT), whereas CUC was enhanced by the addition of recombinant LCAT. Furthermore, CUC correlated with CEC even after being normalized by ApoA1 concentration and was significantly associated with the requirement for revascularization due to the recurrence of coronary lesions. Therefore, our new assay system shows potential for the accurate measurement of CUC in serum and permits assessing cardiovascular health.

Abstract Background Ventricular tachycardia (VT) non‐inducibility at the end of ablation is associated with a less likely VT recurrence. However, it is not clear whether we should use VT non‐inducibility as a routine end point of VT ablation. The aim of this study was to evaluate VT recurrence in patients in whom VT non‐inducibility was not achieved at the end of the radiofrequency (RF) ablation and the factors attributing to the VT recurrence. Methods We analyzed that 62 patients in whom VT non‐inducibility was not achieved at the end of the RF ablation were studied. Results Over 2 years, 22 (35%) of the cases had VT recurrences. A multivariate analysis showed that an LVEF ≥35% (HR: 0.19; 95% CI: 0.06–0.49; p

Abstract Aims With the rapidly increasing ageing population, heart failure is an urgent challenge, particularly in developed countries. The study aimed to investigate the main aetiologies of chronic heart failure in a super‐aged society. Methods and results The KUNIUMI registry chronic cohort is a community‐based, prospective, observational study of chronic heart failure in Awaji Island, Japan. Inhabitants of this island aged ≥65 years accounted for 36.3% of the population. In the present study, data from patients with symptomatic heart failure were extracted from the registry. A total of 1646 patients were enrolled from March 2019 to March 2021, accounting for ~1.3% of the inhabitants of Awaji Island. We analysed 852 patients with symptomatic heart failure. The mean age was high (78.7 ± 11.1 years), with 357 patients (41.9%) being female. The proportion of women increased significantly with advancing age and constituted more than half of the patients aged 85 years and older (P 75 years. Patients with atrial functional mitral regurgitation had a higher prevalence of atrial fibrillation (especially long‐standing persistent atrial fibrillation) and a larger left atrial volume index when compared with patients with other types of mitral regurgitation (P

A young-male underwent radiofrequency (RF) ablation of ventricular premature contractions (VPCs) of over 30,000/day and the morphology exhibited left bundle branch block and a superior axis, which indicated the VPCs originated from the inferior portion of the right ventricle (RV). While the PENTARAY catheter was placed under the tricuspid valve (TV), the earliest potential, which preceded the QRS onset by 34 ms, was recorded. Pace mapping there presented a very similar QRS morphology to the target VPC. However, the radiofrequency (RF)-catheter could not be placed under the TV even when a deflectable sheath was used, because the deflectable curve of the RF-catheter was larger than that of the PENTARAY. An over-the-vale RF application was not effective, so the trans-jugular approach with a deflectable sheath was indicated. The tip of the sheath was placed at a higher portion of the RV cavity to maintain an adequate distance for the RF-catheter tip to be deflected and placed under the TV. With this maneuver, the tip of the RF-catheter was successfully placed under the TV, which was confirmed by intracardiac ultrasound. Small atrial potentials and larger ventricular potentials could be recorded from the distal tip of the RF-catheter, which might indicate that the tip was placed at the TV annulus. An RF application at that site permanently abolished the VPC. Placing the tip of the RF-catheter under the TV by the femoral approach is very difficult in some cases. The trans-jugular approach with a deflectable sheath is one option for arrhythmias from the TV.

Abstract Aims Acute decompensated heart failure (ADHF) is a frequent cause of hospitalization for patients with heart disease, and ADHF patients are at high risk of heart failure (HF) re‐hospitalization. Residual congestion at discharge is also a strong predictor of poor outcomes and re‐hospitalization for ADHF patients. However, the impact of residual congestion at discharge on worsening renal function (WRF) in both high‐aged and older patients remains uncertain because previous studies of WRF in ADHF patients were conducted for older patients. We therefore designed and conducted a retrospective, population‐based study using the Kobe University Heart Failure Registry in Awaji Medical Center (KUNIUMI) Registry to investigate the association of residual congestion at discharge with WRF in ADHF patients according to age. Methods and results We studied 966 hospitalized ADHF patients with a mean age of 80.2 ± 11.4 years from among 1971 listed in the KUNIUMI Registry. WRF was defined as an increase of ≥0.3 mg/dL in the serum creatinine level during the hospital stay compared with the value on admission. The primary endpoint was defined as cardiovascular death or HF re‐hospitalization after discharge over a mean follow‐up period of 2.0 ± 0.1 years. The primary endpoint was recorded for 369 patients (38.2%). As expected, patients with both WRF and residual congestion at discharge had significantly less favourable outcomes compared with those without one of them, and patients without either of these two characteristics had the most favourable outcomes, whereas those with residual congestion and with WRF had the least favourable outcomes. Moreover, WRF was significantly associated with worse outcomes for high‐aged patients ≥80 years old, but not for those

Abstract Background It is uncertain whether cardiac resynchronization therapy with a defibrillator (CRT‐D) provides better survival benefits than a CRT‐pacemaker (CRT‐P) in heart failure patients with a reduced ejection fraction (≦35%, HFrEF) treated with contemporary HF therapy. Methods We retrospectively analyzed the ventricular arrhythmia (VAs; sustained ventricular tachycardia/fibrillation) events in HFrEF patients who underwent CRT without a prior history of VAs or aborted sudden cardiac death before the CRT implantation. Between January/2010 and December/2020, a CRT device was implanted in 79 HFrEF patients (mean age: 69 ± 12 years, male: 57, ischemic cardiomyopathy: 16). CRT‐D and CRT‐P devices were implanted in 50 and 29 patients, respectively, at each physician's discretion. CRT‐Ds were indicated in younger patients than were CRT‐Ps (66 ± 12 vs. 73 ± 12 years, p = 0.03), but the gender distribution did not differ (female, 24% [12 of 50] vs. 35% [10 of 29], p = 0.44). The VA events during a median follow‐up of 3.5‐years (interquartile range [IQR]:1.6–5.5) and their predictors were analyzed. Results VA events occurred in 9 patients with CRT‐Ds (18%) and one with a CRT‐P (3%, p = 0.08). The VA event rate was significantly lower in patients without a prior non‐sustained ventricular tachycardia (NSVT: ≥3 beats; rate, ≥120 bpm; lasting

Abstract Body mass index (BMI) distribution and its impact on cardiovascular disease (CVD) vary between Asian and western populations. The study aimed to reveal time-related trends in the prevalence of obesity and underweight and safe ranges of BMI in Japanese patients with CVD. We analyzed 5,020,464 records from the national Japanese Registry of All Cardiac and Vascular Diseases—Diagnosis Procedure Combination dataset over time (2012–2019) and evaluated BMI trends and the impact on in-hospital mortality for six acute CVDs: acute heart failure (AHF), acute myocardial infarction (AMI), acute aortic dissection (AAD), ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). Patients were categorized into five groups using the WHO Asian-BMI criteria: underweight (

Abstract Background Corticosteroids are widely used in patients with cardiac sarcoidosis (CS). In addition, upgrading to cardiac resynchronization therapy (CRT) is sometimes needed. This study aimed to investigate the impact of corticosteroid use on the clinical outcomes following CRT upgrades. Methods A total of 48 consecutive patients with non‐ischemic cardiomyopathies who underwent CRT upgrades were retrospectively reviewed and divided into three groups: group 1 included CS patients taking corticosteroids before the CRT upgrade (n = 7), group 2, CS patients not taking corticosteroids before the CRT upgrade (n = 10), and group 3, non‐CS patients (n = 31). The echocardiographic response, heart failure hospitalizations, and cardiovascular deaths were evaluated. Results The baseline characteristics during CRT upgrades exhibited no significant differences in the echocardiographic data between the three groups. After the CRT upgrade, responses regarding the ejection fraction (EF) and end‐systolic volume (ESV) were significantly lower in CS patients than non‐CS patients (ΔEF: group 1, 6.7% vs. group 2, 7.7% vs. group 3, 13.6%; p = .039, ΔESV: 3.0 ml vs. ‐12.7 ml vs. ‐37.2 ml; p = .008). The rate of an echocardiographic response was lowest in group 1 (29%). There were, however, no significant differences in the cumulative freedom from a composite outcome among the three groups (p = .19). No cardiovascular deaths occurred in group 1. Conclusion The echocardiographic response to an upgrade to CRT and the long‐term prognosis in patients with CS should be carefully evaluated because of the complex etiologies and impact of immunosuppressive therapy.

Summary: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary artery pressure caused by pathological pulmonary artery remodeling. Here, we demonstrate that endothelial cell (EC) senescence plays a negative role in pulmonary hypertension via juxtacrine interaction with smooth muscle cells (SMCs). By using EC-specific progeroid mice, we discovered that EC progeria deteriorated vascular remodeling in the lungs, and exacerbated pulmonary hypertension in mice. Mechanistically, senescent ECs overexpressed Notch ligands, which resulted in increased Notch signaling and activated proliferation and migration capacities in neighboring SMCs. Pharmacological inhibition of Notch signaling reduced the effects of senescent ECs on SMCs functions in vitro, and improved the worsened pulmonary hypertension in EC-specific progeroid mice in vivo. Our findings show that EC senescence is a critical disease-modifying factor in PAH and that EC-mediated Notch signaling is a pharmacotherapeutic target for the treatment of PAH, particularly in the elderly.

Abstract Knowing the vascular anatomy of the common femoral artery bifurcation and ultrasound‐guided puncture, including doppler, is helpful in recognizing anatomic variations and avoiding complications.

Abstract Background Some of atrial fibrillation (AF) drivers are found in normal/mild late‐gadolinium enhancement (LGE) areas, as well as moderate ones. The atrial wall thickness (AWT) has been reported to be important as a possible AF substrate. However, the AWT and degree of LGEs as an AF substrate has not been fully validated in humans. Objective The purpose of this study was to evaluate the impact of the AWT in normal/mild LGE areas on AF drivers. Methods A total of 287 segments in 15 persistent AF patients were assessed. AF drivers were defined as non‐passively activated areas (NPAs), where rotational activation was frequently observed, and were detected by the novel real‐time phase mapping (ExTRa Mapping), mild LGE areas were defined as areas with a volume ratio of the enhancement voxel of 0% to

Abstract Background Left ventricular (LV) involvement in diabetic cardiomyopathy has been reported; however, only limited data exist on right ventricular (RV) involvement. Therefore, our purpose was to investigate RV systolic dysfunction and its association with LV longitudinal myocardial dysfunction in patients with type 2 diabetes mellitus (T2DM) and preserved LV ejection fraction (LVEF). Methods We studied 177 T2DM patients with preserved LVEF and 79 age-, sex-, and LVEF-matched healthy volunteers. LV longitudinal myocardial function was assessed as global longitudinal strain (GLS), and RV systolic function was assessed as RV free-wall strain, and predefined cutoff values for subclinical dysfunction were set at GLS

A septuagenarian female with cardiac sarcoidosis suffered from drug refractory ventricular tachycardia (VT) requiring multiple implantable cardioverter-defibrillator shocks. The QRS complex during the VT was very similar to that during sinus rhythm although the QRS width during the VT (142 ms) was relatively wider than that during sinus rhythm (107 ms). The VT exit was located on the ventricular septum close to the His-bundle recording region. However, the critical pathway of this VT was detected on the anterior free wall of the left ventricle (LV), and a radiofrequency application at that site could terminate the VT. No Purkinje potentials were recorded there during the VT or sinus rhythm. According to the electrophysiological study, 3-D mapping, and the response to the ablation, the critical circuit of the VT was surrounded by a protected area of scar associated with cardiac sarcoidosis. As a result, the VT circuit was connected to the basal septal area close to the His-Purkinje system as an outer loop of the VT circuit. This unique trajectory of the VT might have caused a similar QRS morphology to that of sinus rhythm, and the relatively narrow QRS complex despite the critical isthmus was located on the anterior free wall of the LV.

Abstract Aims Haemodynamic assessment during stress testing is not commonly performed in patients with heart failure with reduced ejection fraction (HFrEF) because of its invasiveness, lower feasibility, and safety concerns. This study aimed to assess the haemodynamic characteristics of patients with HFrEF in response to non‐invasive preload stress during dynamic postural alterations achieved by combining both semi‐sitting position and passive leg‐lifting and to evaluate whether combined postural stress could be used for risk stratification in these patients. Methods and results For this study, 101 patients with HFrEF and 35 age‐matched and sex‐matched healthy controls were prospectively recruited. After all standard echocardiographic measurements were obtained in the left decubitus position, all subjects underwent postural stress testing, which consisted of changing from semi‐sitting position to passive leg‐lifting. During a median follow‐up period of 12.2 months, 21 (21%) patients developed adverse cardiovascular events. In patients without adverse cardiovascular events, the stroke volume index (SVi) significantly changed from 28 ± 8 to 35 ± 10 mL/m2 (P

Abstract Aims/Introduction Glucose fluctuation (GF) is a residual risk factor for coronary artery disease (CAD). We investigated whether GF influenced clinical outcomes and progression of coronary stenosis in stable CAD patients. Materials and Methods In this prospective study, 101 consecutive lipid‐controlled stable CAD patients underwent percutaneous coronary intervention were enrolled, and GF was expressed as the mean amplitude of glycemic excursion (MAGE) obtained by continuous glucose monitoring before the procedure was evaluated. At 9 months after enrollment, culprit and non‐culprit (mild‐to‐moderate stenosis without ischemia) lesions were serially assessed by angiography. Cardiovascular events (CVE) consisting of cardiovascular death, non‐fatal myocardial infarction or ischemia‐driven revascularization during 2‐year follow up, rapid progression in non‐culprit lesions (defined as ≥10% luminal narrowing progression in lesions with stenosis ≥50%, ≥30% luminal narrowing progression in non‐culprit lesions with stenosis

Compelling evidence suggests a crucial role for Foxp3+ regulatory T cells (Tregs) in the control of atherosclerosis. Although suppression of pro-inflammatory CD4+ T cell immune responses is supposed to be important for athero-protective action of Foxp3+ Tregs, few studies have provided direct evidence for this protective mechanism. We investigated the impact of Foxp3+ Treg depletion on CD4+ T cell immune responses and the development of atherosclerosis under hypercholesterolemia. We employed DEREG (depletion of regulatory T cells) mice on an atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr−/−) background, which carry a diphtheria toxin (DT) receptor under the control of the foxp3 gene locus. In these mice, DT injection led to efficient depletion of Foxp3+ Tregs in spleen, lymph nodes and aorta. Depletion of Foxp3+ Tregs augmented CD4+ effector T cell immune responses and aggravated atherosclerosis without affecting plasma lipid profile. Notably, the proportion of pro-inflammatory IFN-γ-producing T cells were increased in spleen and aorta following Foxp3+ Treg depletion, implying that Foxp3+ Tregs efficiently regulate systemic and aortic T cell-mediated inflammatory responses under hypercholesterolemia. Unexpectedly, Foxp3+ Treg depletion resulted in an increase in anti-inflammatory IL-10-producing T cells, which was not sufficient to suppress the augmented proinflammatory T cell immune responses caused by reduced numbers of Foxp3+ Tregs. Our data indicate that Foxp3+ Tregs suppress pro-inflammatory CD4+ T cell immune responses to control atherosclerosis under hypercholesterolemia.

Background: Right ventricular (RV) afterload is widely assessed by pulmonary vascular resistance (PVR). However, RV afterload is underestimated because PVR does not account for the pulsatile load. The pulsatile load is often evaluated by pulmonary arterial compliance (PAC). The RC (resistance-compliance) time, which is calculated from the product of PVR and PAC, is considered to remain constant under medical therapy. However, little is known on how RC time is affected by invasive therapy in chronic thromboembolic pulmonary hypertension (CTEPH). This study aimed to evaluate change of RC time in patients underwent pulmonary endarterectomy (PEA). Furthermore, we investigated the clinical relevance of RC time. Methods: We reviewed consecutive 50 patients except for death case underwent PEA. Baseline clinical parameters including RC time before performing PEA and follow-up were evaluated. Patients was classified as decrease or non-decrease according to change of RC time. Furthermore, we classified patients into a NYHA I group who had no symptom after treatment and a residual symptom group in order to investigate the relationship of RC time to residual symptoms. Results: RC time was significantly decreased after PEA (0.54 ± 0.16 to 0.45 ± 0.12 sec, p

Abstract Background Left ventricular (LV) longitudinal myocardial dysfunction is considered a marker of preclinical LV dysfunction in patients with type 2 diabetes mellitus (T2DM). High heart rate (HR) is associated with cardiovascular outcomes, but the effect of HR on LV longitudinal myocardial function in T2DM patients is uncertain. Methods We studied 192 T2DM patients with preserved LV ejection fraction (LVEF), and 81 age-, sex-, and LVEF-matched healthy volunteers. HR was measured as the average HR during echocardiography, and high HR was defined as resting HR ≥ 70 beats/minute. LV longitudinal myocardial function was assessed as global longitudinal strain (GLS). The predefined cutoff for subclinical LV dysfunction was set at GLS

Abstract Cardiac accessory pathways (APs) in Wolff–Parkinson–White (WPW) syndrome are conventionally diagnosed with decision tree algorithms; however, there are problems with clinical usage. We assessed the efficacy of the artificial intelligence model using electrocardiography (ECG) and chest X-rays to identify the location of APs. We retrospectively used ECG and chest X-rays to analyse 206 patients with WPW syndrome. Each AP location was defined by an electrophysiological study and divided into four classifications. We developed a deep learning model to classify AP locations and compared the accuracy with that of conventional algorithms. Moreover, 1519 chest X-ray samples from other datasets were used for prior learning, and the combined chest X-ray image and ECG data were put into the previous model to evaluate whether the accuracy improved. The convolutional neural network (CNN) model using ECG data was significantly more accurate than the conventional tree algorithm. In the multimodal model, which implemented input from the combined ECG and chest X-ray data, the accuracy was significantly improved. Deep learning with a combination of ECG and chest X-ray data could effectively identify the AP location, which may be a novel deep learning model for a multimodal model.

Background: Poor oral health status can lead to a deteriorated level of general health and is common among patients undergoing cardiovascular surgery. However, the effect of oral health status on postoperative outcomes in cardiovascular surgery patients remains unclear. Thus, we investigated the effect of preoperative oral health status on postoperative complications and functional recovery after cardiovascular surgery. Methods: This single-centre retrospective cohort study included 884 inpatients undergoing elective cardiovascular surgery. Oral health status was assessed based on the number of remaining teeth, use of dentures, occlusal support, and periodontal status. We investigated postoperative complications related to surgery and postoperative functional recovery by measuring the reacquisition of walking ability, activities of daily living, and length of postoperative hospital stay. Results: In this cohort (age 66.9 ± 13.4 years), the mean number of remaining teeth was 18.7 ± 9.4. Patients were grouped based on tertiles of the data distribution of remaining teeth: ≥ 20 teeth (470 patients); 10-19 teeth (137 patients); < 10 teeth (185 patients). The number of missing teeth was associated with age (P < 0.001). The prevalence of postoperative pneumonia and reintubation after surgery was 3.2% and 2.5%, respectively, which was significantly higher in patients with severe tooth loss (P < 0.05 for both). After adjusting for age and other confounding factors, the number of remaining teeth was a statistically significant predictor of functional recovery (P < 0.05). Conclusions: Preoperative oral health status was related to postoperative respiratory complications and independently associated with functional recovery. Preoperative oral intervention may improve functional recovery after cardiovascular surgery. Résumé: Contexte: Une mauvaise santé buccodentaire peut avoir des répercussions néfastes sur la santé générale et est fréquemment observée chez les patients subissant une intervention chirurgicale cardiovasculaire. Cependant, l’effet de l’état de santé buccodentaire sur les issues postopératoires chez les patients ayant subi une telle intervention est mal connu. Nous avons donc étudié l’effet de l’état de santé buccodentaire avant l’intervention sur les complications postopératoires et le rétablissement fonctionnel après une intervention chirurgicale cardiovasculaire. Méthodologie: Cette étude de cohorte rétrospective menée dans un seul centre réunissait 884 patients subissant une intervention chirurgicale cardiovasculaire non urgente. L’état de santé buccodentaire des patients a été évalué en fonction du nombre de dents restantes, du recours à des prothèses dentaires, de la présence d’appuis occlusaux et de la santé parodontale. Nous avons examiné les cas de complications postopératoires liées à l’intervention chirurgicale ainsi que le rétablissement fonctionnel après l’intervention en évaluant la réacquisition de la capacité de marcher, la capacité d’accomplir les activités de la vie quotidienne et la durée du séjour à l’hôpital après l’intervention. Résultats: Dans cette cohorte (âge moyen : 66,9 ± 13,4 ans), les sujets avaient en moyenne 18,7 ± 9,4 dents restantes. Les patients ont été répartis en trois groupes en fonction du nombre de dents restantes : ≥ 20 dents (470 patients); de 10 à 19 dents (137 patients); < 10 dents (185 patients). Il y avait un lien entre le nombre de dents manquantes et l’âge (p < 0,001). La prévalence des cas de pneumonie postopératoire et de réintubation après l’intervention s’établissait à 3,2 % et à 2,5 %, respectivement, et était significativement plus élevée chez les patients à qui il restait très peu de dents (p < 0,05 dans les deux cas). Après correction pour tenir compte de l’âge et d’autres facteurs de confusion, le nombre de dents restantes s’est révélé être un facteur de prédiction statistiquement significatif du rétablissement fonctionnel (p < 0,05). Conclusions: L’état de santé buccodentaire avant l’intervention chirurgicale était lié à des complications respiratoires postopératoires et associé de manière indépendante au rétablissement fonctionnel. Des soins buccodentaires préopératoires pourraient améliorer le rétablissement fonctionnel après une intervention chirurgicale cardiovasculaire.

Pulmonary arterial hypertension is a progressive fatal disease characterized by pathological pulmonary artery remodeling. Here the authors show that the dysregulation of the activin A-bone morphogenetic protein receptor type 2 link in the endothelium is involved in the progression of pulmonary hypertension.

Abstract Background The impact of reduction in glycemic excursion on coronary plaques remains unknown. This study aimed to elucidate whether a dipeptidyl peptidase 4 inhibitor could reduce the glycemic excursion and stabilize the coronary plaques compared with conventional management in coronary artery disease (CAD) patients with impaired glucose tolerance (IGT). Methods This was a multicenter, randomized controlled trial including CAD patients with IGT under lipid-lowering therapy receiving either vildagliptin (50 mg once a day) or no medication (control group) regarding glycemic treatment. The primary endpoint was changes in the minimum fibrous cap thickness and lipid arc in non-significant native coronary plaques detected by optical coherence tomography at 6 months after intervention. Glycemic variability expressed as the mean amplitude of glycemic excursion (MAGE) measured with a continuous glucose monitoring system was evaluated before and 6 months after intervention. Results A total of 20 participants with 47 lesions were allocated to either the vildagliptin group (10 participants, 22 lesions) or the control group (10 participants, 25 lesions). The adjusted difference of mean changes between the groups was − 18.8 mg/dl (95% confidence interval, − 30.8 to − 6.8) (p = 0.0064) for the MAGE (vildagliptin, − 20.1 ± 18.0 mg/dl vs. control, 2.6 ± 12.7 mg/dl), − 22.8° (− 40.6° to − 5.1°) (p = 0.0012) for the mean lipid arc (vildagliptin, − 9.0° ± 25.5° vs. control, 15.8° ± 16.8°), and 42.7 μm (15.3 to 70.1 μm) (p = 0.0022) for the minimum fibrous cap thickness (vildagliptin, 35.7 ± 50.8 μm vs. control, − 15.1 ± 25.2 μm). Conclusions Vildagliptin could reduce the MAGE at 6 months and may be associated with the decreased lipid arc and increased minimum FCT of the coronary plaques in CAD patients with IGT as compared with the control group. These findings may represent its potential stabilization effect on coronary plaques, which are characteristic in this patient subset. Trial registration Registered in the UMIN clinical trial registry (UMIN000008620), Name of the registry: VOGUE trial, Date of registration: Aug 6, 2012, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000010058

Abstract Background Atrial inflammation plays an important role in initiating atrial fibrosis, which could perpetuate atrial fibrillation (AF). However, the method of visualization of atrial inflammation has not been established. We sought to investigate whether the intensive atrial inflammation caused by cryoballoon ablation (CBA) could be detected by positron emission tomography/ magnetic resonance imaging (PET/MRI) and whether the atrial inflammation could be associated with consequent fibrosis. Methods A total of 10 paroxysmal atrial fibrillation patients after CBA were enrolled. To detect and quantify intensive atrial inflammation, PET/MRI was performed to assess regional 18F‐fluorodeoxyglucose (18F‐FDG) uptake one day after the CBA, and the standardized uptake values (SUV) max were compared between the pulmonary vein (PV) antrum where CBA could be applied and the healthy left atrial (LA) wall where CBA could not be applied. Furthermore, the atrial inflammation one day after the procedure and atrial fibrosis areas one month after the procedure were three‐dimensionally quantified by PET/MRI and late‐gadolinium enhancement magnetic resonance imaging (LGE‐MRI), respectively. Results The mean SUV max at the PV antrum was significantly higher than that on the healthy LA wall (2.12 ± 0.35 vs 1.73 ± 0.30, P = .00021). The volume of the atrial inflammation strongly correlated with that of the atrial fibrosis (r = .94 [.76‐.99], P = .00006). Conclusions The atrial inflammation after CBA could be detected by PET/MRI. CBA‐induced atrial inflammation was strongly associated with consequent lesion maturation.

Background Cardiac extracellular matrix is critically involved in cardiac homeostasis, and accumulation of chondroitin sulfate glycosaminoglycans (CS‐GAGs) was previously shown to exacerbate heart failure by augmenting inflammation and fibrosis at the chronic phase. However, the mechanism by which CS‐GAGs affect cardiac functions remains unclear, especially at the acute phase. Methods and Results We explored a role of CS‐GAG in heart failure using mice with target deletion of ChGn‐2 (chondroitin sulfate N‐acetylgalactosaminyltransferase‐2) that elongates CS chains of glycosaminoglycans. Heart failure was induced by transverse aortic constriction in mice. The role of CS‐GAG derived from cardiac fibroblasts in cardiomyocyte death was analyzed. Cardiac fibroblasts were subjected to cyclic mechanical stretch that mimics increased workload in the heart. Significant CS‐GAGs accumulation was detected in the heart of wild‐type mice after transverse aortic constriction, which was substantially reduced in ChGn‐2‐/‐ mice. Loss of ChGn‐2 deteriorated the cardiac dysfunction caused by pressure overload, accompanied by augmented cardiac hypertrophy and increased cardiomyocyte apoptosis. Cyclic mechanical stretch increased ChGn‐2 expression and enhanced glycosaminoglycan production in cardiac fibroblasts. Conditioned medium derived from the stretched cardiac fibroblasts showed cardioprotective effects, which was abolished by CS‐GAGs degradation. We found that CS‐GAGs elicits cardioprotective effects via dual pathway; direct pathway through interaction with CD44, and indirect pathway through binding to and activating insulin‐like growth factor‐1. Conclusions Our data revealed the cardioprotective effects of CS‐GAGs; therefore, CS‐GAGs may play biphasic role in the development of heart failure; cardioprotective role at acute phase despite its possible unfavorable role in the advanced phase.

Background Clinical outcomes of acute myocardial infarction complicated by cardiogenic shock remain poor with high in‐hospital mortality. Veno‐arterial extracorporeal membrane oxygenation (VA‐ECMO) has been widely used for patients with acute myocardial infarction complicated by cardiogenic shock refractory to conservative therapy, which is likely fatal without mechanical circulatory support. However, whether additional intra‐aortic balloon pumping (IABP) use during VA‐ECMO support improves clinical outcomes remains controversial. This study sought to investigate prognostic impact of the combined VA‐ECMO plus IABP treatment compared with VA‐ECMO alone. Methods and Results From the nationwide Japanese administrative case‐mix Diagnostic Procedure Combination (DPC), the JROAD (Japanese Registry of All Cardiac and Vascular Diseases)–DPC, we identified 3815 patients with acute myocardial infarction complicated by cardiogenic shock who underwent primary percutaneous coronary intervention and managed with VA‐ECMO. Of these, 2964 patients (77.7%) were managed with IABP (VA‐ECMO plus IABP), whereas 851 (22.3%) were managed without IABP (VA‐ECMO alone). We compared in‐hospital, 7‐day, and 30‐day mortality between the VA‐ECMO plus IABP versus the VA‐ECMO alone support. Patients managed with VA‐ECMO plus IABP demonstrated significantly lower in‐hospital, 7‐day, and 30‐day mortality than those managed with VA‐ECMO alone (adjusted odds ratios [95% CI] of 0.47 [95% CI, 0.38–0.59], 0.41 [95% CI, 0.33–0.51], and 0.30 [95% CI, 0.25–0.37], respectively). The findings were consistent in the propensity matching and inverse probability of treatment‐weighting models. Conclusions This large‐scale, nationwide study demonstrated that the combination of VA‐ECMO plus IABP support was associated with significantly lower mortality compared with VA‐ECMO support alone in patients presenting with acute myocardial infarction complicated by cardiogenic shock who underwent primary percutaneous coronary intervention.

Abstract Background Left ventricular (LV) longitudinal dysfunction has been identified in type 2 diabetes mellitus (T2DM) patients with preserved LV ejection fraction (LVEF). However, the impact of T2DM on LV longitudinal function or the association of LV longitudinal function with outcome for dilated cardiomyopathy (DCM) remains unclear. Methods We retrospectively studied 206 patients with non-ischemic DCM, mean age of 59 ± 17 years and LVEF of 31 ± 8% (all

Abstract Background Balloon aortic valvuloplasty (BAV) offers an alternative to conventional aortic valve replacement in elderly and frail patients with severe aortic stenosis (AS) for whom there are no other effective options. We aimed to investigate the mid-term effect of BAV on mitral regurgitation (MR) in patients with severe AS. Methods Our analysis was based on the data from 83 patients with severe AS (mean age, 86 ± 5 years; female, 68) treated using BAV. Echocardiography was performed before the procedure and at 1 and 3 months after. MR was quantified by measuring the MR jet area, with more-than-moderate MR being clinically significant. Results Forty patients were classified in this group (MR group). Significant reduction of MR was observed in the MR group at 1 month and 3 months after procedure, with no improvement in patients in the non-MR group. At 3 months, 15 of the 40 patients in the MR group still had significant MR, with the change at 1 month in the left ventricular end-systolic dimension (OR: 1.36; 95% CI: 1.05–1.76; P = 0.022) and MR jet area (OR: 1.95; 95% CI: 1.16–3.29; P = 0.012) being predictive of persisting significant MR at 3 months after BAV. The prevalence of New York Heart Association functional class III or IV decreased at 1 and 3 months after BAV in both groups. Conclusions BAV provides a useful therapeutic strategy for elderly patients with severe AS who are not candidates for surgical or transcatheter aortic valve replacement, especially in those with significant MR.

Abstract Background The effect of sodium glucose cotransporter type 2 (SGLT2) inhibitor on left ventricular (LV) longitudinal myocardial function in type 2 diabetes mellitus (T2DM) patients with heart failure (HF) has remained unclear. Methods We analyzed data from our previous prospective multicenter study, in which we investigated the effect of the SGLT2 inhibitor dapagliflozin on LV diastolic functional parameters of T2DM patients with stable HF at five institutions in Japan. Echocardiography was performed at baseline and 6 months after administration of dapagliflozin. LV diastolic function was defined as the ratio of mitral inflow E to mitral e′ annular velocities (E/e′). LV longitudinal myocardial function was assessed as global longitudinal strain (GLS), which in turn was determined as the averaged peak longitudinal strain from standard LV apical views. Results E/e′ significantly decreased from 9.3 to 8.5 cm/s 6 months after administration of dapagliflozin (p = 0.020) as previously described, while GLS showed significant improvement from 15.5 ± 3.5% to 16.9 ± 4.1% (p

Vascular senescence is closely associated with individual ageing, while its causative role remains unclear. Here Barinda et al. generate endothelial cell-specific progeroind mice, and reveal that endothelial cell senescence directly induces metabolic disorders through senescence-messaging secretomes.

BackgroundRecent studies have suggested that chronic kidney disease is associated with cardiovascular disease, dementia, and frailty, all of which cause disability and early death. We investigated whether increased activity of urinary N-acetyl-β-glucosaminidase (NAG), a marker of kidney injury, is associated with risk of disability or all-cause mortality in a general population.MethodsFollow-up data from the Hidaka Cohort Study, a population-based cohort study of members of a Japanese rural community, were obtained via questionnaires completed by participants or their relatives. Multivariable analyses were used to investigate relations between urinary NAG activity-urinary creatinine concentration ratio and risk of disability or all-cause mortality.ResultsA total of 1182 participants were followed up for a median of 12.4 years. The endpoints were receipt of support under the public long-term care insurance program, and all-cause mortality. A total of 122 participants (10.3%) were reported to be receiving long-term care and 230 (19.5%) had died. After adjustment for cardiovascular risk factors along with physical activity, and using the quartile 1 results as a reference, the odds ratio (OR) for disability was 2.12 [95% confidence interval (95% confidence interval [CI]), 1.04-4.33; p = 0.038) and the hazard ratio (HR) for all-cause mortality was 1.65 (95% CI, 1.05-2.62; p = 0.031) in participants with urinary NAG/creatinine ratio in quartile 4. Similar results were obtained in participants without proteinuria: OR for disability, 2.46 (95% CI, 1.18-5.16; p = 0.017); and HR for all-cause mortality, 1.62 (95% CI, 1.00-2.63; p = 0.049).ConclusionsIncreased urinary NAG/creatinine ratio was associated with risk of disability or all-cause mortality in a general population.

Abstract Background Type 2 diabetes mellitus (T2DM) is a major cause of heart failure (HF) with preserved ejection fraction (HFpEF), usually presenting as left ventricular (LV) diastolic dysfunction. Thus, LV diastolic function should be considered a crucial marker of a preclinical form of DM-related cardiac dysfunction. However, the impact of glycemic variability (GV) on LV diastolic function in such patients remains unclear. Methods We studied 100 asymptomatic T2DM patients with preserved LV ejection fraction (LVEF) without coronary artery disease (age: 60 ± 14 years, female: 45%). GV was evaluated as standard deviation of blood glucose level using continuous glucose monitoring system for at least 72 consecutive hours. LV diastolic function was defined as mitral inflow E and mitral e’ annular velocities (E/e’), and > 14 was determined as abnormal. Results E/e’ in patients with high GV (≥ 35.9 mg/dL) was significantly higher than that in patients with low GV (11.3 ± 3.9 vs. 9.8 ± 2.8, p = 0.03) despite similar age, gender-distribution, and hemoglobin A1c (HbA1c). Multivariate logistic regression analysis showed that GV ≥ 35.9 mg/dL (odds ratio: 3.67; 95% confidence interval: 1.02–13.22; p 14. In sequential logistic models for the associations of LV diastolic dysfunction, one model based on clinical variables including age, gender and hypertension was not improved by addition of HbA1c (p = 0.67) but was improved by addition of high GV (p = 0.04). Conclusion Since HFpEF is a syndrome caused by diverse agents, reducing GV may represent a potential new therapeutic strategy for the prevention of the development of HFpEF in T2DM patients.

Summary: The gut microbiome has emerged as a key regulator of obesity; however, its role in brown adipose tissue (BAT) metabolism and association with obesity remain to be elucidated. We found that the levels of circulating branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) were significantly correlated with the body weight in humans and mice and that BCAA catabolic defects in BAT were associated with obesity in diet-induced obesity (DIO) mice. Pharmacological systemic enhancement of BCAA catabolic activity reduced plasma BCAA and BCKA levels and protected against obesity; these effects were reduced in BATectomized mice. DIO mice gavaged with Bacteroides dorei and Bacteroides vulgatus exhibited improved BAT BCAA catabolism and attenuated body weight gain, which were not observed in BATectomized DIO mice. Our data have highlighted a possible link between the gut microbiota and BAT BCAA catabolism and suggest that Bacteroides probiotics could be used for treating obesity.

Aims: Circulating amino acid (AA) abnormalities serve as predictors of adverse outcomes in patients with heart failure (HF). However, the role of the gut microbiota in AA disturbances remains unknown. Thus, we investigated gut microbial functions and their associations with AA metabolic alterations in patients with HF.Methods and Results: We performed whole-genome shotgun sequencing of fecal samples and mass spectrometry-based profiling of AAs in patients with compensated HF. Plasma levels of total essential AAs (EAAs) and histidine were significantly lower in patients with HF than in control subjects. HF patients also displayed increased and decreased abundance of gut microbial genes involved in the degradation and biosynthesis, respectively, of EAAs, including branched-chain AAs (BCAAs) and histidine. Importantly, a significant positive correlation was observed between the abundance of microbial genes involved in BCAA biosynthesis and plasma BCAA levels in patients with HF, but not in controls. Moreover, network analysis revealed that the depletion of Eubacterium and Prevotella, which harbor genes for BCAA and histidine biosynthesis, contributed to decreased abundance of microbial genes involved in the biosynthesis of those EAAs in patients with HF.Conclusions: The present study demonstrated the relationship between gut microbiota and AA metabolic disturbances in patients with HF.

Objectives Predictive algorithms to inform risk management decisions are needed for patients with COVID-19, although the traditional risk scores have not been adequately assessed in Asian patients. We aimed to evaluate the performance of a COVID-19-specific prediction model, the 4C (Coronavirus Clinical Characterisation Consortium) Mortality Score, along with other conventional critical care risk models in Japanese nationwide registry data.Design Retrospective cohort study.Setting and participants Hospitalised patients with COVID-19 and cardiovascular disease or coronary risk factors from January to May 2020 in 49 hospitals in Japan.Main outcome measures Two different types of outcomes, in-hospital mortality and a composite outcome, defined as the need for invasive mechanical ventilation and mortality.Results The risk scores for 693 patients were tested by predicting in-hospital mortality for all patients and composite endpoint among those not intubated at baseline (n=659). The number of events was 108 (15.6%) for mortality and 178 (27.0%) for composite endpoints. After missing values were multiply imputed, the performance of the 4C Mortality Score was assessed and compared with three prediction models that have shown good discriminatory ability (RISE UP score, A-DROP score and the Rapid Emergency Medicine Score (REMS)). The area under the receiver operating characteristic curve (AUC) for the 4C Mortality Score was 0.84 (95% CI 0.80 to 0.88) for in-hospital mortality and 0.78 (95% CI 0.74 to 0.81) for the composite endpoint. It showed greater discriminatory ability compared with other scores, except for the RISE UP score, for predicting in-hospital mortality (AUC: 0.82, 95% CI 0.78 to 0.86). Similarly, the 4C Mortality Score showed a positive net reclassification improvement index over the A-DROP and REMS for mortality and over all three scores for the composite endpoint. The 4C Mortality Score model showed good calibration, regardless of outcome.Conclusions The 4C Mortality Score performed well in an independent external COVID-19 cohort and may enable appropriate disposition of patients and allocation of medical resources.Trial registration number UMIN000040598.

Background Myocardial extracellular volume fraction (ECV), measured by cardiac magnetic resonance imaging, is a useful prognostic marker for patients who have undergone aortic valve replacement (AVR) for aortic stenosis. However, the prognostic significance of ECV measurements based on computed tomography (CT) is unclear. This study evaluated the association between ECV measured with dual‐energy CT and clinical outcomes in patients with aortic stenosis who underwent transcatheter or surgical AVR. Methods and Results We retrospectively enrolled 95 consecutive patients (age, 84.0±5.0 years; 75% women) with severe aortic stenosis who underwent preprocedural CT for transcatheter AVR planning. ECV was measured using iodine density images obtained by delayed enhancement dual‐energy CT. The primary end point was a composite outcome of all‐cause death and hospitalization for heart failure after AVR. The mean ECV measured with CT was 28.1±3.8%. During a median follow‐up of 2.6 years, 22 composite outcomes were observed, including 15 all‐cause deaths and 11 hospitalizations for heart failure. In Kaplan‐Meier analysis, the high ECV group (≥27.8% [median value]) had significantly higher rates of composite outcomes than the low ECV group (

Background Although patients with a cancer history have a 2 to 3 times higher risk for acute coronary syndrome (ACS), the morphological characteristics of ACS culprit plaque in those patients and their relations with clinical outcomes remain unknown. Methods and Results This retrospective, multicenter, observational cohort study included consecutive patients with ACS who underwent optical coherence tomography‐guided emergent percutaneous coronary intervention. Patients were categorized into those without a cancer history, those with a cancer history, and those currently receiving cancer treatment. ACS culprit lesions were classified as plaque rupture, plaque erosion, or calcified nodule using optical coherence tomography. Plaque erosion frequency was significantly higher in culprit lesions of patients with current cancer and patients with cancer history than in those of patients without cancer history (56.3% versus 61.7% versus 36.5%). Calcified nodule incidence was significantly higher in patients without cancer history than in patients with current cancer and patients without cancer history (patients with current cancer: 12.4% versus patients without cancer history: 25.5% versus patients without cancer history: 12.6%, P

Abstract A 61‐year‐old female with 50 000 ventricular premature contractions and a reduced left ventricular ejection fraction of 35% was referred to our center. Although the origin was considered to originate from the junction between the left and right coronary cusp, a single radiofrequency application above the aortic sinus cusp could eliminate it. LGE‐MRI was able to reveal the exact location of the single RF lesion.

Abstract Atrial tachycardia (AT) in the right atrium often occurs following open‐heart surgery. Catheter ablation for these AT is challenging and can lead to unintended conduction block. We performed late‐gadolinium enhancement magnetic resonance imaging (LGE‐MRI) prior to catheter ablation and predicted wavefront propagation during SR as well as the slow conduction zone during tachycardia. LGE‐MRI may assist predicting the conduction disturbance and reducing the risk of unexpected sinus exit block.

Abstract Background Although anticoagulation therapy could reduce the risk of strokes in patients with atrial fibrillation (AF), large‐scale investigations in the direct oral anticoagulant (DOAC) and AF catheter ablation (CA) era are lacking. Methods This study was designed as a prospective, multicenter, observational study and a total of 2113 patients from 22 institutions were enrolled in the Hyogo area. Results The mean age and CHADS2 score were 70.1 ± 10.8 years old and 1.5 ± 1.1, respectively. The follow‐up period was 355 ± 43 days. CA was performed in 614 (29%) and DOACs were prescribed in 1118 (53%) patients. Ischemic strokes/systemic embolisms (SEs) and major bleeding occurred in 13 (0.6%) and 17 (0.8%) patients, respectively. New onset dementia, hospitalizations for cardiac events, and all‐cause death occurred in eight (0.4%), 60 (2.8%), and 29 (1.4%) patients, respectively. A multivariate analysis demonstrated that persistent AF and the body weight (BW) were associated with ischemic strokes/SEs and major bleeding, respectively (persistent AF: hazard ratio, 9.57; 95%CI, 1.2‐74.0; P = .03; BW: hazard ratio, 0.94; 95%CI, 0.90‐0.99; P = .02). AFCA history was associated with the cardiac events (hazard ratio, 0.44; 95%CI, 0.20‐0.99; P = .04). Age was associated with new onset dementia (hazard ratio, 1.1; 95%CI, 1.0‐1.2; P = .03). Conclusions In the DOAC and CA era, the incidence of ischemic strokes/SEs, major bleeding and cardiac events could be dramatically reduced in patients with AF. However, some unsolved issues of AF management still remain especially in elderly patients with persistent AF and a low BW.

Abstract A 41‐year‐old man with persistent atrial fibrillation (AF) underwent radiofrequency (RF) catheter ablation using an online real‐time phase mapping system: ExTRa Mapping. Box isolation could not terminate AF. Subsequently, RF applications on nonpassively activated areas (NPAs), where rotational activations were frequently observed, at the posterior bottom of left atrium outside of box lesion could convert AF to common atrial flutter. Of interest, the NPA near the posterior bottom were located on the patchy fibrotic tissue area assessed by the late‐gadolinium enhancement magnetic resonance imaging. This indicated the possibility of the critical AF rotor meandering through the fibrotic tissue area.

Background Medium‐dose (25 gray) x‐ray radiation therapy has recently been performed on patients with refractory ventricular tachyarrhythmias. Unlike x‐ray, carbon ion and proton beam radiation can deliver most of their energy to the target tissues. This study investigated the electrophysiological and pathological changes caused by medium‐dose carbon ion and proton beam radiation in the left ventricle (LV). Methods and Results External beam radiation in the whole LV was performed in 32 rabbits. A total of 9 rabbits were not irradiated (control). At the 3‐month or 6‐month follow‐up, the animals underwent an open‐chest electrophysiological study and were euthanized for histological analyses. No acute death occurred. Significant LV dysfunction was not seen. The surface ECG revealed a significant reduction in the P and QRS wave voltages in the radiation groups. The electrophysiological study showed that the local conduction times in each LV site were significantly longer and that the local LV bipolar voltages were significantly lower in the radiation groups than in the control rabbits. Histologically, apoptosis, fibrotic changes, and a decrease in the expression of the connexin 43 protein were seen in the LV myocardium. These changes were obvious at 3 months, and the effects were sustained 6 months after radiation. No histological changes were seen in the coronary artery and esophagus, but partial radiation pneumonitis was observed. Conclusions Medium‐dose carbon ion and proton beam radiation in the whole LV resulted in a significant electrophysiological disturbance and pathological changes in the myocardium. Radiation of the arrhythmogenic substrate would modify the electrical status and potentially induce the antiarrhythmic effect.