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Abstract Aims Congestive heart failure (HF) is a common complication in patients with acute myocardial infarction (AMI). The estimated plasma volume status [ePVS = (100 − haematocrit)/haemoglobin] is used as the blood plasma volume index to determine the presence of congestion in patients with HF. However, the clinical impact of ePVS at discharge in patients with AMI remains unclear. This study aimed to investigate whether ePVS at discharge could determine the long‐term prognosis in patients with AMI. Methods and results We retrospectively identified patients with AMI with ePVS measured at discharge between January 2012 and December 2020. The primary endpoint was post‐discharge all‐cause death. The patients were divided into two groups according to an ePVS cut‐off value of 5.5%, which is commonly used in HF. In total, 1012 patients with AMI were included. The median age was 70 years (range, 61–78 years), and 76.4% of the patients were male. The ePVS > 5.5% (high‐ePVS) group included 365 patients (36.1%), and the all‐cause mortality rate in the total cohort was 17.7%. The log‐rank test revealed that the high‐ePVS group had a significantly higher rate of all‐cause death than the ePVS ≤ 5.5% (low‐ePVS) group (P

Abstract Estimated glomerular filtration rate (eGFR) variation is associated with end-stage kidney disease (ESKD) development in patients with chronic kidney disease; whether annual variations in eGFR at health check-ups is associated with ESKD risk in the general population is unclear. We conducted a retrospective cohort study using Japanese national medical insurance claims from 2013 to 2020. Individuals who had their eGFR levels measured three times in annual health check-ups were included (N = 115,191), and the coefficient of variation of eGFR (CVeGFR) was calculated from 3-point eGFR. The end-point was ESKD as reported in the claims data. We analyzed the association between CVeGFR and ESKD incidence after adjusting for conventional ESKD risk factors. The CVeGFR median distribution was 5.7% (interquartile range: 3.5–8.5%). During a median follow-up period of 3.74 years, 164 patients progressed to ESKD. ESKD incidence was significantly higher in the highest quartile group (CVeGFR ≥ 8.5%) than in the other groups (P

Abstract Cardiac sarcoidosis (CS) is the scarring of heart muscles by autoimmunity, leading to heart abnormalities and patients with sarcoidosis with cardiac involvements have poor prognoses. Due to the small number of patients, it is difficult to stratify all patients of CS by human leukocyte antigen (HLA) analysis. We focused on the structure of antigen-recognizing pockets in heterodimeric HLA-class II, in addition to DNA sequences, and extracted high-affinity combinations of antigenic epitopes from candidate autoantigen proteins and HLA. Four HLA heterodimer-haplotypes (DQA1*05:03/05:05/05:06/05:08-DQB1*03:01) were identified in 10 of 68 cases. Nine of the 10 patients had low left ventricular ejection fraction (

Abstract Aims Heart failure (HF) with preserved ejection fraction (HFpEF) is a complex syndrome with a poor prognosis. Phenotyping is required to identify subtype‐dependent treatment strategies. Phenotypes of Japanese HFpEF patients are not fully elucidated, whose obesity is much less than Western patients. This study aimed to reveal model‐based phenomapping using unsupervised machine learning (ML) for HFpEF in Japanese patients. Methods and results We studied 365 patients with HFpEF (left ventricular ejection fraction >50%) as a derivation cohort from the Nara Registry and Analyses for Heart Failure (NARA‐HF), which registered patients with hospitalization by acute decompensated HF. We used unsupervised ML with a variational Bayesian–Gaussian mixture model (VBGMM) with common clinical variables. We also performed hierarchical clustering on the derivation cohort. We adopted 230 patients in the Japanese Heart Failure Syndrome with Preserved Ejection Fraction Registry as the validation cohort for VBGMM. The primary endpoint was defined as all‐cause death and HF readmission within 5 years. Supervised ML was performed on the composite cohort of derivation and validation. The optimal number of clusters was three because of the probable distribution of VBGMM and the minimum Bayesian information criterion, and we stratified HFpEF into three phenogroups. Phenogroup 1 (n = 125) was older (mean age 78.9 ± 9.1 years) and predominantly male (57.6%), with the worst kidney function (mean estimated glomerular filtration rate 28.5 ± 9.7 mL/min/1.73 m2) and a high incidence of atherosclerotic factor. Phenogroup 2 (n = 200) had older individuals (mean age 78.8 ± 9.7 years), the lowest body mass index (BMI; 22.78 ± 3.94), and the highest incidence of women (57.5%) and atrial fibrillation (56.5%). Phenogroup 3 (n = 40) was the youngest (mean age 63.5 ± 11.2) and predominantly male (63.5 ± 11.2), with the highest BMI (27.46 ± 5.85) and a high incidence of left ventricular hypertrophy. We characterized these three phenogroups as atherosclerosis and chronic kidney disease, atrial fibrillation, and younger and left ventricular hypertrophy groups, respectively. At the primary endpoint, Phenogroup 1 demonstrated the worst prognosis (Phenogroups 1–3: 72.0% vs. 58.5% vs. 45%, P = 0.0036). We also successfully classified a derivation cohort into three similar phenogroups using VBGMM. Hierarchical and supervised clustering successfully showed the reproducibility of the three phenogroups. Conclusions ML could successfully stratify Japanese HFpEF patients into three phenogroups (atherosclerosis and chronic kidney disease, atrial fibrillation, and younger and left ventricular hypertrophy groups).

Background Although a tool for sharing patient prognosis among all medical staff is desirable in heart failure (HF) cases, only a few simple HF prognostic scores are available. We previously presented the A2B score, a simple user‐friendly HF risk score, and validated it in a small single‐center cohort. In the present study, we validated it in a larger nationwide cohort. Methods and Results We examined the 2‐year mortality in relation to the A2B scores in 3483 patients from a Japanese nationwide cohort and attempted to stratify their prognoses according to the scores. The A2B score was determined by assigning points for age, anemia, and brain natriuretic peptide (BNP) level at discharge: age (

Abstract Clinical scenario 1 (CS1) is acute heart failure (HF) characterized by transient systolic blood pressure (SBP) elevation and pulmonary congestion. Although it is managed by vasodilators, the molecular mechanism remains unclear. The sympathetic nervous system plays a key role in HF, and desensitization of cardiac β-adrenergic receptor (AR) signaling due to G protein-coupled receptor kinase 2 (GRK2) upregulation is known. However, vascular β-AR signaling that regulates cardiac afterload remains unelucidated in HF. We hypothesized that upregulation of vascular GRK2 leads to pathological conditions similar to CS1. GRK2 was overexpressed in vascular smooth muscle (VSM) of normal adult male mice by peritoneally injected adeno-associated viral vectors driven by the myosin heavy chain 11 promoter. Upregulation of GRK2 in VSM of GRK2 overexpressing mice augmented the absolute increase in SBP (+ 22.5 ± 4.3 mmHg vs. + 36.0 ± 4.0 mmHg, P

Abstract Diagnosis of calcified nodules (CNs) is critical in the proper management of coronary artery disease, but CNs can be detected only using intracoronary imaging modalities. This study aimed to investigate the ability of coronary computed tomography angiography (CCTA) in predicting CNs detected using optical coherence tomography (OCT). From 138 patients who underwent OCT-guided percutaneous coronary intervention (PCI) after CCTA evaluation, 141 PCI target vessels were retrospectively enrolled and classified into CN (12 vessels/11 patients; CNs in the PCI culprit lesion) and non-CN (129 vessels/127 patients; without CNs) groups based on the OCT analysis. Retrospective CCTA analysis revealed significantly higher coronary artery calcification score (CACS), calcified plaque volume (CPV), and maximum calcified plaque area (MCPA) of the target vessel in the CN group than in the non-CN group. Receiver operating characteristic curve indicated that CACS ≥ 162 (area under the ROC curve (AUC 0.76, sensitivity 83.3%, specificity 54.2%), CPV ≥ 20.1 mm3 (AUC 0.83, sensitivity 100%, specificity 57.3%), and MCPA ≥ 4.51 mm2 (AUC 0.87, sensitivity 91.7%, specificity 78.3%) were the best cutoff values for predicting CNs. MCPA showed the highest AUC among all the CCTA parameters. In conclusion, CCTA is useful for predicting OCT-detected CNs in PCI target vessels.

Abstract Background Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscular disorder characterized by asymmetric muscle wasting and weakness. FSHD can be subdivided into two types: FSHD1, caused by contraction of the D4Z4 repeat on chromosome 4q35, and FSHD2, caused by mild contraction of the D4Z4 repeat plus aberrant hypomethylation mediated by genetic variants in SMCHD1, DNMT3B, or LRIF1. Genetic diagnosis of FSHD is challenging because of the complex procedures required. Methods We applied Nanopore CRISPR/Cas9-targeted resequencing for the diagnosis of FSHD by simultaneous detection of D4Z4 repeat length and methylation status at nucleotide level in genetically-confirmed and suspected patients. Results We found significant hypomethylation of contracted 4q-D4Z4 repeats in FSHD1, and both 4q- and 10q-D4Z4 repeats in FSHD2. We also found that the hypomethylation in the contracted D4Z4 in FSHD1 is moderately correlated with patient phenotypes. Conclusions Our method contributes to the development for the diagnosis of FSHD using Nanopore long-read sequencing. This finding might give insight into the mechanisms by which repeat contraction causes disease pathogenesis.

Abstract Aims Cancer therapy‐related cardiac dysfunction (CTRCD) is commonly reported, but its histopathology, mechanisms, and risk factors are not known. We aimed to clarify the histopathology and mechanisms of CTRCD to identify risk factors. Methods and results We performed myocardial histopathological studies on 13 endomyocardial biopsies from CTRCD patients, 35 autopsied cancer cases with or without cardiac dysfunction, and controls without cancer (10 biopsies and 9 autopsies). Cardiotoxicity risk scores were calculated based on medication; and patient‐related risk factors, fibrosis, and cardiomyocyte changes were scored; and p53 and H3K27ac histone modification were evaluated by histological score (H‐score). In the biopsy cases, all histopathological changes and the p53 evaluation were significantly higher in the CTRCD group than in the controls [p53 H‐score; 63 (9.109) vs. 33 (5.099), P 4.2 years), cellular abnormalities and p53 trended to a positive correlation and cardiotoxicity risk scores and p53 positively correlated (r = 0.95, P

Abstract We clarified the association between changes in the number of foundational medications for heart failure (FMHF) during hospitalization for worsening heart failure (HF) and post-discharge prognosis. We retrospectively analyzed a combined dataset from three large-scale registries of hospitalized patients with HF in Japan (NARA-HF, WET-HF, and REALITY-AHF) and patients diagnosed with HF with reduced or mildly reduced left ventricular ejection fraction (HFr/mrEF) before admission. Patients were stratified by changes in the number of prescribed FMHF classes from admission to discharge: angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor blockers. Primary endpoint was the combined endpoint of HF rehospitalization and all-cause death within 1 year of discharge. The cohort comprised 1113 patients, and 482 combined endpoints were observed. Overall, FMHF prescriptions increased in 413 (37.1%) patients (increased group), remained unchanged in 607 (54.5%) (unchanged group), and decreased in 93 (8.4%) (decreased group) at discharge compared with that during admission. In the multivariable analysis, the increased group had a significantly lower incidence of the primary endpoint than the unchanged group (hazard ratio 0.56, 95% confidence interval 0.45–0.60; P

Introduction The incidence of arrhythmia in heart failure with non-reduced ejection fraction (HFnon-rEF) in patients who have a history of hospitalisation is unclear. The aim of this study is to investigate the usefulness of an implantable loop recorder (ILR) for arrhythmia detection including atrial fibrillation (AF) in HFnon-rEF patients after discharge.Methods and analysis This is a multicentre single arm study to evaluate the usefulness of ILR for detecting arrhythmia. The eligible patients are HFnon-rEF patients (left ventricular ejection fraction ≥40%) aged ≥20 years with a history of hospitalisation. The ILR will be implanted for qualified patients, and ECGs will be monitored and recorded for 1 year to check for arrhythmias. The primary endpoint is new-onset 6 min or more persistent AF detected by ILR. Secondary endpoints are 30 s or more persistent supraventricular tachycardia and ventricular tachycardia, 3 s or more persistent pause, bradycardia with 40 beats per minutes or lower heart rate, AF burden, all-cause death, cardiovascular death, hospital readmission due to exacerbation of HF, acute coronary syndrome, ischaemic or haemorrhagic stroke, non-pharmacological therapy such as pacemaker implantation and ablation.Conclusions This study is expected to provide valuable findings regarding arrhythmia in HFnon-rEF patients, and elucidate a potential new therapeutic approach for HFnon-rEF.Trial registration number This trial has been registered in the Japan Registry of Clinical Trials (jRCT) (Trial Registration: jRCTs052210060).

Abstract This study sought to develop a deep learning-based diagnostic algorithm for plaque vulnerability by analyzing intravascular optical coherence tomography (OCT) images and to investigate the relation between AI-plaque vulnerability and clinical outcomes in patients with coronary artery disease (CAD). A total of 1791 study patients who underwent OCT examinations were recruited from a multicenter clinical database, and the OCT images were first labeled as either normal, a stable plaque, or a vulnerable plaque by expert cardiologists. A DenseNet-121-based deep learning algorithm for plaque characterization was developed by training with 44,947 prelabeled OCT images, and demonstrated excellent differentiation among normal, stable plaques, and vulnerable plaques. Patients who were diagnosed with vulnerable plaques by the algorithm had a significantly higher rate of both events from the OCT-observed segments and clinical events than the patients with normal and stable plaque (log-rank p

Abstract Background There is a lack of recent data reflecting the actual use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for heart failure (HF) and type 2 diabetes (DM) in the superaged society. The present study investigated the association between the use of SGLT2 inhibitors and one-year prognosis in patients hospitalized across a broad spectrum of HF patients with DM in the superaged society using the Nationwide Electric Health Database in Japan. Methods The patients hospitalized with the first episode of acute HF were identified from the National Database of Health Insurance Claims and Specific Health Checkups of Japan between April 2014 and March 2019. A cohort of 2,277 users of SGLT2 inhibitors and 41,410 users of the active comparator, dipeptidyl peptidase-4 (DPP4) inhibitors were compared. A propensity score-matched cohort study of 2,101 users of each inhibitor was also conducted. A multivariable multilevel mixed-effects survival model was conducted with adjustments, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Results Among 300,398 patients discharged with HF in 4,176 hospitals, 216,016 (71.9%) were 75 years or older, and 60,999 (20.3%) took antidiabetic medications. Among them, the patients treated with SGLT2 inhibitors were younger and had a more severe status than those treated with DPP4 inhibitors. Kaplan–Meier analysis showed that patients treated with SGLT2 inhibitors had a lower mortality risk and HF readmission. In propensity-matched cohorts, SGLT2 inhibitor use was associated with a lower risk of mortality and HF readmission than DPP-4 inhibitor use (HR [95% CI]; 0.70 [0.56, 0.89] and 0.52 [0.45, 0.61], respectively). Very elderly (≥ 75 years) patients showed similar results. Favorable effects were also observed across all age groups, including ≥ 75 years, in patients with coronary artery disease or atrial fibrillation and with concomitant β-blocker, diuretics, or insulin. Conclusion The use of SGLT2 inhibitors at discharge was associated with a lower risk of one-year mortality and HF readmission in patients across a broad spectrum of HF with DM in the superaged society. The findings further support the benefits of using SGLT2 inhibitors in very elderly HF care and complement the current evidence.

Abstract Aims Increased left ventricular mass index (LVMI) disproportionate to electrocardiographic QRS voltage has been reported to be associated with cardiac fibrosis and amyloid infiltration to myocardium. This study aimed to assess whether the LVMI‐to‐QRS‐voltage ratio predicts clinical outcomes in heart failure with preserved ejection fraction (HFpEF). Methods and results The Japanese Heart Failure Syndrome with Preserved Ejection Fraction (JASPER) registry is a nationwide, observational, and prospective registration of Japanese patients hospitalized with HFpEF (EF ≥ 50%). LVMI was assessed by echocardiography using the cube formula. QRS voltage was assessed by Sokolow–Lyon voltage criteria. We divided 290 patients in the registry who met inclusion criteria into five groups according to the quintile values of their LVMI‐to‐QRS‐voltage ratio. In the highest quintile group (≥71.8 g/m2/mV), approximately 50% of the patients had concentric hypertrophy and 30% had eccentric hypertrophy. These patients had the highest proportion of atrial fibrillation (61.4%) and history of pacemaker implantation (12.1%) among the five groups (P

Abstract Aims Acute heart failure (AHF) is a clinical syndrome with a poor prognosis and a major public health concern worldwide. The aim of this study was to investigate whether carperitide administration improves the 1 year prognosis of patients with AHF and to check whether there is an optimal dose of the drug. Methods and results We analysed the data of COOPERATE‐HF‐J (the Consortium for Pooled Data Analysis regarding Hospitalized Patients with Heart Failure in Japan), combining two cohorts (NARA‐HF and REALITY‐AHF), which included 2435 patients with acute decompensated heart failure. The patients were divided into no carperitide (NO‐ANP, n = 1098); very low‐dose carperitide (VLD‐ANP,

Abstract Background When performing an electrical isolation of ipsilateral pulmonary veins (PVs) for atrial fibrillation, physicians often need additional radiofrequency (RF) ablation in the carina region between the superior and inferior PVs to achieve a right PV isolation because of intercaval bundles between the right PVs and right atrium (RA). We compared the efficacy of a high‐power and short‐duration ablation guided by unipolar signal modification (UM) with the conventional method (CM) for ablating epicardial connections between the right PV carina and RA. Methods The study subjects consisted of patients who underwent an initial box isolation of atrial fibrillation from January 2015 to December 2019 at Nara Medical University Hospital. Among these patients, 94 and 65 patients who met the criteria were assigned to the CM and UM groups, respectively. We retrospectively analyzed the anterior ablation line of the right PV using an electroanatomical mapping system. Patients whose initial ablation line included the right PV carina were excluded. Results Six and seven patients were, respectively, excluded from the CM and UM groups. Among 88 CM group patients, 21 needed additional right PV carina ablation, while among 58 UM group patients, 30 needed additional right PV carina ablation (p = .001). No anatomical factors were associated with the additional right PV carina ablation. Conclusions Compared to the CM group, a box isolation was less achievable without RF ablation at the right PV carina in the UM group. We should consider a long‐duration ablation for epicardial connections between the right PV carina and RA.

Background The fractional excretion of urea nitrogen (FEUN) has been used as a renal blood flow index related to cardiac output, and the estimated plasma volume status (ePVS) as a body fluid volume index. However, the usefulness of their combination in acute decompensated heart failure (HF) management is unclear. We investigated the effect of 4 hemodynamic categories according to the high and low FEUN and ePVS values at discharge on the long‐term prognosis of patients with acute decompensated HF. Methods and Results Between April 2011 and December 2018, we retrospectively identified 466 patients with acute decompensated HF with FEUN and ePVS values at discharge. Primary end point was postdischarge all‐cause death. Secondary end points were (1) the composite of all‐cause death and HF readmission, and (2) HF readmission in a time‐to‐event analysis. The patients were divided into 4 groups according to the high/low FEUN (≥35%, 5.5%, ≤5.5%) values at discharge: high‐FEUN/low‐ePVS, high‐FEUN/high‐ePVS, low‐FEUN/low‐ePVS, and low‐FEUN/high‐ePVS groups. During a median follow‐up period of 28.1 months, there were 173 all‐cause deaths (37.1%), 83 cardiovascular deaths (17.8%), and 121 HF readmissions (26.0%). The Kaplan–Meier curve analysis showed that the high‐FEUN/low‐ePVS group had a better prognosis than the other groups (log‐rank test, P

Aims: Real-world evidence about heart failure (HF) medical care for elderly patients is limited. The aim of this study was to clarify the age-dependent associations of HF medications at discharge with clinical outcomes in a super-aged society using a real-world big database. Methods and results: Patients hospitalized with a first episode of acute HF in 2013–2019 were identified in a nationwide claims database in Japan and were analyzed based on the HF medications at discharge. Hazard ratios (HRs) and 95 % confidence intervals (95 % CIs) for clinical outcomes were calculated after adjustment. Among 325,468 patients from 4351 hospitals, 130,230 (40.0 %) were aged ≥ 85 years. All-cause mortality and HF readmission rate within 1 year were 14 % and 23 %, respectively. β-Blockers and angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers (ACEI/ARB) uses were associated with lower mortality (HR [95 %CI]: 0.84 [0.83,0.86] and 0.73 [0.71,0.74], respectively) and HF readmission (0.98 [0.97,0.99] and 0.89 [0.88,0.90], respectively). The associations were attenuated as the age increased and, in β-blockers use, the favorable associations with mortality and HF readmission were not observed in patients with ≥ 95 years and ≥ 80 years, respectively. In contrast, mineralocorticoid receptor antagonists (MRA) use was associated only with lower HF readmission (0.83 [0.82,0.84]), which was not attenuated with increased age. Conclusions: The favorable associations of β-blockers and ACEI/ARB uses with mortality and HF readmission were age-dependently attenuated in patients across a broad spectrum of HF in a super-aged society. In contrast, positive impact of MRA use on HF readmission was not attenuated with aging.

Abstract Aims Patients undergoing dialysis, even those without coronary artery disease or valvular abnormalities, sometimes present with reduced heart function, which resembles dilated cardiomyopathy (DCM). This condition is known as uraemic cardiomyopathy (UCM). The mechanisms of UCM development are not fully understood. Previous studies demonstrated that the balance between placental growth factor (PlGF) and fms‐like tyrosine kinase‐1 (Flt‐1) is correlated with renal function, and PlGF/Flt‐1 signalling is involved in the development of cardiovascular diseases in patients with chronic kidney disease. This study was conducted to evaluate the pathogenesis of UCM and clarify the differences in the mechanisms of UCM and DCM by using human endomyocardial biopsy and blood samples. Methods and results The clinical and pathological features of 30 patients on dialysis with reduced cardiac function [left ventricular ejection fraction (LVEF) ≤50%] (UCM group; mean age: 58.5 ± 9.4 years and LVEF: 39.1 ± 7.2%), 196 DCM patients (DCM group; mean age: 62.7 ± 14.0 years and LVEF: 33.5 ± 8.8%) as controls with reduced cardiac function (LVEF ≤ 45%), and 21 patients as controls with normal cardiac function (control group; mean age: 56.2 ± 19.3 years and LVEF: 67.5 ± 6.7%) were analysed. The percentage of the interstitial fibrosis area in the UCM group was greater than that in the DCM group (P = 0.045). In UCM patients, the percentage of the interstitial fibrosis area was positively correlated with the duration of renal replacement therapy (P

Abstract Background Collagen VI-related dystrophy spans a clinical continuum from severe Ullrich congenital muscular dystrophy to milder Bethlem myopathy. This disease is caused by causative variants in COL6A1, COL6A2, or COL6A3. Most reported causative variants are de novo; therefore, to identify possible associated causative variants, comprehensive large cohort studies are required for different ethnicities. Methods We retrospectively reviewed clinical information, muscle histology, and genetic analyses from 147 Japanese patients representing 130 families, whose samples were sent for diagnosis to the National Center of Neurology and Psychiatry between July 1979 and January 2020. Genetic analyses were conducted by gene-based resequencing, targeted panel resequencing, and whole exome sequencing, in combination with cDNA analysis. Results Of a total of 130 families with 1–5 members with collagen VI-related dystrophy, 120 had mono-allelic and 10 had bi-allelic variants in COL6A1, COL6A2, or COL6A3. Among them, 60 variants were in COL6A1, 57 in COL6A2, and 23 in COL6A3, including 37 novel variants. Mono-allelic variants were classified into four groups: missense (69, 58%), splicing (40, 33%), small in-frame deletion (7, 6%), and large genomic deletion (4, 3%). Variants in the triple helical domains accounted for 88% (105/120) of all mono-allelic variants. Conclusions We report the causative variant profile of a large set of Japanese cases of collagen VI-related dystrophy. This dataset can be used as a reference to support genetic diagnosis and variant-specific treatment.

Abstract Aims Patients who survive acute myocardial infarction (AMI) are at risk of being rehospitalized owing to the occurrence of acute decompensated heart failure (HF). However, the clinical characteristics of HF after AMI, especially the frequency of each HF subtype, are unclear. Methods and results We retrospectively studied 1055 patients with AMI. We excluded 257 patients, who were admitted >48 h after the onset of AMI, died during hospitalization or after discharge, and whose echocardiogram data at index hospitalization and follow‐up data were missing. The remaining 798 patients (mean age: 66.5 ± 11.7 years) were investigated for a mean follow‐up period of 4.9 years. All patients underwent emergency coronary angiography. The mean maximum creatine kinase levels were 2898 ± 2627 IU/L, and mean left ventricular ejection fraction (LVEF) was 58.9 ± 10.2%. Eighty‐one patients (10.2%) were rehospitalized because of unexpected worsening of HF. Echocardiography data were available for 74 of the 81 patients during the acute phase of the second hospitalization, of which 30, 20, and 24 patients (41%, 27%, and 32%, respectively) were diagnosed as having HF with preserved LVEF (LVEF ≥ 50%), HF with mid‐range LVEF (40% ≤ LVEF

Abstract Iron is an essential trace element in the body. However, in heart failure (HF), iron is only recognized as the cause of anemia. Actually, iron itself affects myocardial exercise tolerance and cardiac function via mitochondrial function. Therefore, it is necessary to clarify the pathological significance of iron in acute HF, irrespective of concomitant anemia. We investigated the impact of serum iron level at discharge on the prognosis of 615 patients emergently admitted with acute decompensated HF (ADHF). Patients were divided into two groups according to the median level of serum iron (62 µg/dL). The endpoint was the composite outcome, which included all-cause mortality and readmission for HF. During the mean follow-up period of 32.1 months, there were 333 events. Kaplan–Meier analysis showed that the incidence of the composite outcome was significantly higher in the Low iron group (P

Abstract Aims This study aimed to investigate the influence of climatic factors on the onset of Takotsubo syndrome (TTS). Methods and results We performed a retrospective nationwide study among patients registered in the Japanese Registry of All Cardiac and Vascular Diseases and Diagnosis Procedure Combination (JROAD–DPC) discharge database, between 2012 and 2016. Before the analysis, a multicentre validation study was conducted for assessing the accuracy of the JROAD–DPC classification for TTS. First, we investigated the seasonal variation of incidences of TTS. Second, we analysed the associations between the incidence of TTS and climatic factors using the hierarchical Poisson regression modelling, and we also investigated the associations between typhoon landfalls and hospitalization for TTS, using the fixed‐effects conditional Poisson regression model. The sensitivity and specificity for diagnosis were 83% and 100%, respectively. Then we analysed 5643 patients with TTS. The mean patient age was 74 (standard deviation ± 11) years; 79% were female. TTS was diagnosed significantly more frequently in the summer and early autumn. The incidence of TTS was related to higher temperatures; adjusted incidence rate ratios were 1.46 [95% confidence interval (CI): 1.33–1.60, P 25°C, respectively. The incidence rate ratio for the first 2 days after a typhoon landfall was 1.85 (95% CI: 1.07–3.19; P = 0.03). Conclusions This study demonstrates distinct patterns of seasonal variation in the incidence of TTS, as well as a significant association between its onset and climatic factors, including typhoon landfalls.

Abstract Aims A sodium glucose cotransporter 2 (SGLT2) inhibitor was recently found to reduce heart failure hospitalization in the EMPA‐REG OUTCOME trial. We have hypothesized that autonomic nerve activity may be modulated by SGLT2 inhibition. The current study aims to investigate the impact of empagliflozin on sympathetic and parasympathetic nerve activity in patients with type 2 diabetes mellitus. Methods and results This ongoing study is a prospective, randomized, open‐label, multicentre investigation of 134 patients with type 2 diabetes mellitus. The patients are randomly allocated to receive either empagliflozin or sitagliptin with the treatment goal of the Japan Diabetes Society guidelines. Ambulatory electrocardiographic monitoring is performed at the baseline and at 12 and 24 weeks of treatment. Analyses of heart rate variability are conducted using the MemCalc method, which is a combination of the maximum entropy method for spectral analysis and the non‐linear least squares method for square analysis. The primary endpoint is the change in the low‐frequency (0.04–0.15 Hz)/high‐frequency (0.15–0.4 Hz) ratio from baseline to 24 weeks. Conclusions This investigation on the effect of EMPagliflozin on cardiac sYmpathetic and parasympathetic neRve activity in JapanEse pAtieNts with type 2 diabetes (EMPYREAN study) offers an important opportunity to understand the impact of SGLT2 inhibition on autonomic nerve activity in patients with type 2 diabetes.

Abstract Aims The prognostic implication of left ventricular outflow tract velocity time integral (LVOT‐VTI) on admission in hospitalized heart failure with preserved ejection fraction (HFpEF) patients has not been determined. We sought to investigate whether LVOT‐VTI on admission is associated with worse clinical outcomes in hospitalized patients with HFpEF. Methods and results We studied consecutive 214 hospitalized HFpEF patients who had accessible LVOT‐VTI data on admission, from a prospective HFpEF‐specific multicentre registry. The primary outcome of interest was the composite of all‐cause death and readmission due to heart failure. During a median follow‐up period of 688 (interquartile range 162–810) days, the primary outcome occurred in 83 patients (39%). The optimal cut‐off value of LVOT‐VTI for the primary outcome estimated by receiver operating characteristic analysis was 15.8 cm. Lower LVOT‐VTI was significantly associated with the primary outcome compared with higher LVOT‐VTI (P = 0.005). Multivariable Cox regression analyses revealed that lower LVOT‐VTI was an independent determinant of the primary outcome (hazard ratio 0.94, 95% confidence interval 0.91–0.98). In multivariable linear regression, haemoglobin level was the strongest independent determinant of LVOT‐VTI among clinical parameters (β coefficient = −0.61, P = 0.007). Furthermore, patients with lower LVOT‐VTI and anaemia had the worst clinical outcomes among the groups (P < 0.001). Conclusions Lower admission LVOT‐VTI was an independent determinant of worse clinical outcomes in hospitalized HFpEF patients, indicating that LVOT‐VTI on admission might be useful for categorizing a low‐flow HFpEF phenotype and risk stratification in hospitalized HFpEF patients.

Activation of the classical complement pathway plays a major role in regulating atherosclerosis progression, and it is believed to have both proatherogenic and atheroprotective effects. This study focused on C1q, the first protein in the classical pathway, and examined its potentialities of plaque progression and instability and its relationship with clinical outcomes. To assess the localization and quantity of C1q expression in various stages of atherosclerosis, immunohistochemistry, western blotting, and real-time polymerase chain reaction (PCR) were performed using abdominal aortas from eight autopsy cases. C1q immunoreactivity in relation to plaque instability and clinical outcomes was also examined using directional coronary atherectomy (DCA) samples from 19 patients with acute coronary syndromes (ACS) and 18 patients with stable angina pectoris (SAP) and coronary aspirated specimens from 38 patients with acute myocardial infarction. C1q immunoreactivity was localized in the extracellular matrix, necrotic cores, macrophages and smooth muscle cells in atherosclerotic lesions. Western blotting and real-time PCR illustrated that C1q protein and mRNA expression was significantly higher in advanced lesions than in early lesions. Immunohistochemical analysis using DCA specimens revealed that C1q expression was significantly higher in ACS plaques than in SAP plaques. Finally, immunohistochemical analysis using thrombus aspiration specimens demonstrated that histopathological C1q in aspirated coronary materials could be an indicator of poor medical condition. Our results indicated that C1q is significantly involved in atherosclerosis progression and plaque instability, and it could be considered as one of the indicators of cardiovascular outcomes.

Placental growth factor (PlGF) and its receptor, fms-like tyrosine kinase-1 (Flt-1), are important regulators involved in angiogenesis, atherogenesis, and inflammation. This review article focuses on the function of PlGF/Flt-1 signaling and its regulation by soluble Flt-1 (sFlt-1) in chronic kidney disease (CKD). Elevation of circulating sFlt-1 and downregulation of sFlt-1 in the vascular endothelium by uremic toxins and oxidative stress both exacerbate heart failure and atherosclerosis. Circulating sFlt-1 is inconsistent with sFlt-1 synthesis, because levels of matrix-bound sFlt-1 are much higher than those of circulating sFlt-1, as verified by a heparin loading test, and are drastically reduced in CKD.

Background Maintaining euvolemia is crucial for improving prognosis in acute decompensated heart failure (ADHF). Although fractional excretion of urea nitrogen (FEUN) is used as a body fluid volume index in patients with acute kidney injury, the clinical impact of FEUN in patients with ADHF remains unclear. This study aimed to investigate whether FEUN can determine the long‐term prognosis in patients with ADHF. Methods and Results We retrospectively identified 466 patients with ADHF who had FEUN measured at discharge between April 2011 and December 2018. The primary endpoint was post‐discharge all‐cause death. Patients were divided into two groups according to a FEUN cut‐off value of 35%, commonly used in pre‐renal failure. The FEUN

LMNA is one of the leading causative genes of genetically inherited dilated cardiomyopathy (DCM). Unlike most DCM-causative genes, which encode sarcomeric or sarcomere-related proteins, LMNA encodes nuclear envelope proteins, lamin A and C, and does not directly associate with contractile function. However, a mutation in this gene could lead to the development of DCM. The molecular mechanism of how LMNA mutation contributes to DCM development remains largely unclear and yet to be elucidated. The objective of this study was to clarify the mechanism of developing DCM caused by LMNA mutation.Methods and Results: We assessed cardiomyocyte phenotypes and characteristics focusing on cell cycle activity in mice with Lmna mutation. Both cell number and cell size were reduced, cardiomyocytes were immature, and cell cycle activity was retarded in Lmna mutant mice at both 5 weeks and 2 years of age. RNA-sequencing and pathway analysis revealed “proliferation of cells” had the most substantial impact on Lmna mutant mice. Cdkn1a, which encodes the cell cycle regulating protein p21, was strongly upregulated in Lmna mutants, and upregulation of p21 was confirmed by Western blot and immunostaining. DNA damage, which is known to upregulate Cdkn1a, was more abundantly detected in Lmna mutant mice. To assess the proliferative capacity of cardiomyocytes, the apex of the neonate mouse heart was resected, and recovery from the insult was observed. A restricted cardiomyocyte proliferating capacity after resecting the apex of the heart was observed in Lmna mutant mice.Conclusions: Our results strongly suggest that loss of lamin function contributes to impaired cell proliferation through cell cycle defects. The inadequate inborn or responsive cell proliferation capacity plays an essential role in developing DCM with LMNA mutation.

Background: Anemia and chronic kidney disease (CKD) are common in patients with heart failure with preserved left ventricular fraction (HFpEF). However, it is entirely unknown about the impact of anemia on prognosis in HFpEF patients with CKD. In this study, we investigated the impact of anemia on prognosis and the optimal hemoglobin (Hb) levels to predict prognosis in HFpEF patients with CKD. Methods and Results: We prospectively examined 523 consecutive HFpEF patients enrolled in Japanese heart failure syndrome with preserved ejection fraction registry. CKD was defined as an estimated glomerular filtration rate (eGFR) of

Abstract Aims Heart failure (HF) is classified into three types according to left ventricular ejection fraction (EF). The effect of blood pressure (BP) on the pathogenesis of each type is assumed to be different. However, the association between the prognosis of each type of HF and abnormal BP variations assessed by ambulatory BP monitoring (ABPM), such as nocturnal hypertension and the riser pattern, remains unclear. Methods and results We studied 325 consecutive patients with decompensated HF who were acutely admitted to our hospital and underwent ABPM at discharge. During a mean follow‐up of 30.0 months, 52 cardiovascular and 112 all‐cause deaths occurred. The Cox proportional hazards model showed that the mean values of 24 h, awake, and sleep‐time systolic BP (SBP), and abnormal 24 h ABPM patterns, such as nocturnal hypertension and non‐dipper pattern, were not associated with either all‐cause or cardiovascular mortality in patients with HF with reduced EF (HFrEF), HF with mid‐range EF (HFmrEF), or HF with preserved EF (HFpEF), except for sleep‐time SBP in HFrEF. However, the riser pattern was a significant and independent predictor of all‐cause and cardiovascular deaths in patients with HFpEF (hazard ratio, 2.01; 95% confidence interval, 1.12–3.62; 0.0200; and hazard ratio, 2.48; 95% confidence interval, 1.08–5.90; 0.0332, respectively). Sleep‐time pulse rate was similarly decreased in both the riser and non‐riser groups. Conclusions The riser pattern of SBP was associated with an increased risk of adverse outcomes among patients with HFpEF but not HFrEF or HFmrEF.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) activate the guanylyl cyclase A receptor (GC-A), which synthesizes the second messenger cGMP in a wide variety of tissues and cells. C-type natriuretic peptide (CNP) activates the cGMP-producing guanylyl cyclase B receptor (GC-B) in chondrocytes, endothelial cells, and possibly smooth muscle cells, cardiomyocytes, and cardiac fibroblasts. The development of genetically modified mice has helped elucidate the physiological roles of natriuretic peptides via GC-A or GC-B. These include the hormonal effects of ANP/BNP in the vasculature, autocrine effects of ANP/BNP in cardiomyocytes, and paracrine effects of CNP in the vasculature and cardiomyocytes. Neprilysin (NEP) is a transmembrane neutral endopeptidase that degrades the three natriuretic peptides. Recently, mice overexpressing NEP, specifically in cardiomyocytes, revealed that local cardiac NEP plays a vital role in regulating natriuretic peptides in the heart tissue. Since NEP inhibition is a clinically accepted approach for heart failure treatment, the physiological roles of natriuretic peptides have regained attention. This article focuses on the physiological roles of natriuretic peptides elucidated in mice with GC-A or GC-B deletion, the significance of NEP in natriuretic peptide metabolism, and the long-term effects of angiotensin receptor-neprilysin inhibitor (ARNI) on cardiovascular diseases.

In recent years, the necessity of free-space optical (FSO) communications has increased as a method for realizing high-speed communications between satellites and the ground. However, one disadvantage of FSO communications is the significant influence of the atmosphere. Specifically, FSO communications cannot be utilized under certain atmospheric conditions, especially in the presence of clouds. One of the solutions to this problem is the site diversity technique, which makes it possible to select a given ground station with better atmospheric conditions among a number of fixed ground stations. The other solution is to prepare a ground station that can be moved to a place with better atmospheric conditions. We applied the latter method and developed a transportable optical ground station in NICT. We utilize a realistic telescope diameter, which is about 30 cm at the maximum, capable of being set up quickly, and with a pointing accuracy of about 100 µrad. In addition, it is necessary to prepare a fine-pointing optical system that performs tracking with about 1/10 of the pointing accuracy of the telescope. In this paper, we report the results of the first performance test of the transportable optical ground station in NICT.

Nemaline myopathy is a heterogeneous disorder of skeletal muscle, and histologically characterized by the presence of nemaline bodies in muscle fibers. Patients with typical congenital form of nemaline myopathy initially present with proximal but later also distal muscle weakness, mostly involving facial and respiratory muscle. Cardiac involvement has been rarely observed especially in nebulin-related nemaline myopathy and there have been only two reports about nebulin-related nemaline myopathy patients with cardiac involvement. We present here the case of a 65-year-old woman manifesting slowly progressive distal myopathy with respiratory and heart failure. She harbored two variants in the nebulin gene, c.20131C > T (p.Arg6711Trp) and c.674C > T (p.Pro225Leu), and one of them, c.674C > T, was a novel variant. In this report, we discuss the pathogenicity of the novel variant and its association with clinical phenotypes including cardiac involvement.

Introduction There are fewer reports about whether the presence of hematuria affects the progression of chronic kidney disease in patients with diabetic nephropathy. We analyzed whether microscopic hematuria in diabetic nephropathy is a risk factor for end-stage kidney disease (ESKD).Research design and methods The present study was a retrospective cohort study of patients with biopsy-proven diabetic nephropathy. We recruited 397 patients with diabetic nephropathy, which was confirmed by renal biopsy between June 1981 and December 2014 and followed them until October 2018 or death. Patients with microscopic hematuria before renal biopsy were defined as the hematuria group (n=91), and the remainder as the no-hematuria group (n=306). The main outcome was the occurrence of ESKD, which was defined by the requirement of permanent renal replacement therapies.Results The systolic and diastolic blood pressure, serum creatinine and proteinuria were significantly higher, and the estimated glomerular filtration rate was significantly lower in the hematuria group compared with the no-hematuria group. Pathological evaluations revealed that glomerular, tubulointerstitial and vascular lesions in the hematuria group were significantly more severe. During a median of 10.1 years, 44 and 52 patients developed ESKD in the hematuria group and the no-hematuria group, respectively. Survival analyses showed that the incidence of ESKD was significantly higher in the hematuria group compared with the no-hematuria group (log-rank, p

BACKGROUND Vascular healing response associated with adjunctive n‐3 polyunsaturated fatty acid therapy therapy in patients receiving strong statin therapy remains unclear. The aim of this study was to evaluate the effect of polyunsaturated fatty acid therapy with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) in addition to strong statin therapy on coronary atherosclerotic plaques using optical coherence tomography. METHODS AND RESULTS This prospective multicenter randomized controlled trial included 130 patients with acute coronary syndrome treated with strong statins. They were assigned to either statin only (control group, n=42), statin+high‐dose EPA (1800 mg/day) (EPA group, n=40), statin+EPA (930 mg/day)+DHA (750 mg/day) (EPA+DHA group, n=48). Optical coherence tomography was performed at baseline and at the 8‐month follow‐up. The target for optical coherence tomography analysis was a nonculprit lesion with a lipid plaque. Between baseline and the 8‐month follow‐up, fibrous cap thickness (FCT) significantly increased in all 3 groups. There were no significant differences in the percent change for minimum FCT between the EPA or EPA+DHA group and the control group. In patients with FCT

Background Insulin beneficially affects myocardial functions during myocardial ischemia. It increases glucose‐derived ATP production, decreases oxygen consumption, suppresses apoptosis of cardiomyocytes, and promotes the survival of cardiomyocytes. Patients with chronic heart failure generally have high insulin resistance, which is correlated with poor outcomes. The role of insulin in acute decompensated heart failure (ADHF) remains unclear. This study aimed to investigate the prognostic value of serum insulin level at the time of admission for long‐term outcomes in patients with ADHF. Methods and Results We enrolled 1074 consecutive patients who were admitted to our department for ADHF. Of these 1074 patients, we studied the impact of insulin on the prognosis of ADHF in 241 patients without diabetes mellitus. The patients were divided into groups according to low, intermediate, and high tertiles of serum insulin levels. Primary end points were all‐cause death and cardiovascular death. During a mean follow‐up of 21.8 months, 71 all‐cause deaths and 38 cardiovascular deaths occurred. Kaplan–Meier analysis showed that all‐cause and cardiovascular mortality was significantly higher in the low‐insulin group than those in the intermediate‐ and high‐insulin groups (log‐rank P=0.0046 and P=0.038, respectively). Moreover, according to the multivariable analysis, low serum insulin was an independent predictor of all‐cause and cardiovascular mortality (hazard ratio, 2.37 [95% CI, 1.24–4.65; P=0.009] and 2.94 [95% CI, 1.12–8.19; P=0.028], respectively). Conclusions Low serum insulin levels were associated with increased risk of all‐cause and cardiovascular death in ADHF patients without diabetes mellitus.

Background Plaque erosion is responsible for 25% to 40% of patients with acute coronary syndromes (ACS). Recent studies suggest that anti‐thrombotic therapy without stenting may be an option for this subset of patients. Currently, however, an invasive procedure is required to make a diagnosis of plaque erosion. The aim of this study was to identify clinical or laboratory predictors of plaque erosion in patients with ACS to enable a diagnosis of erosion without additional invasive procedures. Methods and Results Patients with ACS who underwent optical coherence tomography imaging were selected from 11 institutions in 6 countries. The patients were classified into plaque rupture, plaque erosion, or calcified plaque, and predictors were identified using multivariable logistic modeling. Among 1241 patients with ACS, 477 (38.4%) patients were found to have plaque erosion. Plaque erosion was more frequent in non–ST‐segment elevation‐ACS than in ST‐segment–elevation myocardial infarction (47.9% versus 29.8%, P=0.0002). Multivariable logistic regression models showed 5 independent parameters associated with plaque erosion: age 15.0 g/dL, and normal renal function. When all 5 parameters are present in a patient with non–ST‐segment elevation‐ACS, the probability of plaque erosion increased to 73.1%. Conclusions Clinical and laboratory parameters associated with plaque erosion are explored in this retrospective registry study. These parameters may be useful to identify the subset of ACS patients with plaque erosion and guide them to conservative management without invasive procedures. The results of this exploratory analysis need to be confirmed in large scale prospective clinical studies. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03479723.

Background Little evidence is available about the number of cardiologists required for appropriate treatment of heart failure (HF). Our objective was to determine the association between the number of cardiologists per cardiology beds for treating patients with acute HF and in‐hospital mortality. Methods and Results This was a cross‐sectional study, and we used the Japanese Registry of All Cardiac and Vascular Diseases Diagnosis Procedure Combination discharge database. The data of patients with HF on emergency admission from April 1, 2012, to March 31, 2014, were extracted. The patients were categorized into 4 groups by the quartiles of the numbers of cardiologists per 50 cardiovascular beds (first group: median, 4.4 [interquartile range, 3.5–5.0]; second group: median, 6.7 [interquartile range, 6.5–7.5]; third group: median, 9.7 [interquartile range, 8.8–10.1]; and fourth group: median, 16.7 [interquartile range, 14.0–23.8]). Using multilevel mixed‐effect logistics regression, we determined adjusted odds ratios for in‐hospital mortality. We identified 154 290 patients with HF on emergency admissions. There were 29 626, 36 587, 46 451, and 41 626 patients in the first, second, third, and fourth groups, respectively. HF severity, on the basis of New York Heart Association classification, was similar in the 3 groups. Adjusted odds ratios (95% CIs) for in‐hospital mortality were 0.92 (0.82–1.04; P=0.20), 0.82 (0.72–0.92; P

Background The JROAD‐DPC (Japanese Registry of All Cardiac and Vascular Diseases Diagnosis Procedure Combination) is a nationwide claims database comprised of the Japanese DPC/Per Diem Payment System. This study aimed to investigate the relationship between prescription rates of guideline‐directed medications in each hospital and in‐hospital mortality among patients with acute myocardial infarction. Methods and Results A total of 61 838 Japanese patients from 741 hospitals with acute myocardial infarction between 2012 and 2013 were enrolled. The relationship between prescription rates of 4 guideline‐directed medications for acute myocardial infarction and in‐hospital mortality was analyzed. There were variations in the prescription ratio of β‐blockers on admission (median prescription rate 23% [interquartile range 11% to 38%]) and at discharge (51% [36% to 63%]), and of angiotensin converting enzyme/receptor blocker (60% [47% to 70%]). The highest prescription rate quartile of each medication was associated with a significantly lower mortality compared with the lowest prescription rate quartile (aspirin on admission, incidence rate ratio 0.67 [95% CI 0.61‐0.74], P

Restrictive cardiomyopathy (RCM) is a rare form of cardiomyopathy that is characterized by restrictive ventricular filling. Elevated filling pressure leads to pulmonary hypertension (PH), which often progresses to combined post- and pre-capillary PH (Cpc-PH) with increased diastolic pulmonary vascular pressure gradient (DPG) and pulmonary vascular resistance (PVR) caused by longstanding backward hemodynamic consequences of left heart disease (LHD) leading to morphological changes in the pulmonary vasculature. Patients with high PVR undergoing left ventricular assist device (LVAD) implantation are at increased risk of postoperative right-sided heart failure requiring concomitant implantation of a right ventricular assist device (RVAD). We report a case of RCM with severe Cpc-PH due to extremely elevated DPG and PVR. The patient presented recurrent syncope caused by severe PH. Right heart catheterization (RHC) revealed highly elevated DPG 30 mmHg and PVR 25.3 Wood units (WU) and subsequent significant reduction of right ventricular afterload during vasoreactivity testing with inhaled nitric oxide (NO) to DPG 5 mmHg and PVR 10.5 WU. During the administration of pulmonary vasodilators, pulmonary congestion worsened. Second RHC revealed elevated pulmonary arterial wedge pressure (PAWP) and modest decrease of pulmonary arterial pressure (PAP) 87 mmHg and PVR 9.6 WU. Therefore, an inotropic agent and systemic vasodilator were added for the treatment of left-sided heart failure. Targeting elevated filling pressures with both PAH-specific and heart failure treatment, a further decrease of right ventricular afterload with DPG of 5 mmHg and PVR of 3.8 WU was achieved. In a next step, LVAD was successfully implanted, without need for RVAD, as a bridge to transplantation. This is the first reported case of Cpc-PH that revealed the potential reversibility of extremely elevated DPG and PVR, and suggests the importance of preoperative RHC-guided optimized medical PAH-specific and heart failure treatment before LVAD implantation.

Objective: In optical coherence tomography (OCT)-guided percutaneous coronary intervention (PCI), stent size is usually determined according to the pre-PCI lumen size of either the distal or proximal reference site. However, the effect of the OCT imaging catheter crossing the target lesion on the reference lumen measurements has not been studied. We evaluated changes in the reference lumen size before and after PCI using frequency domain OCT. Methods: For 100 consecutive patients with PCI, mean lumen diameter (LD) and lumen area (LA) were measured at the proximal and distal reference sites before and after coronary stent implantation with OCT. Results: Mean LD and LA of the distal reference site were significantly increased after PCI with stent implantation (2.57 ± 0.6 to 2.62 ± 0.64 mm, p 1.50 mm2. Tissue characteristics were not correlated with changes in reference lumen size. Conclusions: When we select the stent size during OCT-guided PCI, we need to pay attention to the decrease in the luminal measurement of the reference sites, especially in lesions with tight stenosis.

BackgroundUrinary neutrophil gelatinase‐associated lipocalin (U‐NGAL) is an early predictor of acute kidney injury and adverse events in various diseases; however, in acute decompensated heart failure patients, its significance remains poorly understood. This study aimed to investigate the prognostic value of U‐NGAL on the first day of admission for the occurrence of acute kidney injury and long‐term outcomes in acute decompensated heart failure patients. Methods and ResultsWe studied 260 acute decompensated heart failure patients admitted to our department between 2011 and 2014 by measuring U‐NGAL in 24‐hour urine samples collected on the first day of admission. Primary end points were all‐cause death, cardiovascular death, and heart failure admission. Patients were divided into 2 groups according to their median U‐NGAL levels (32.5 μg/gCr). The high‐U‐NGAL group had a significantly higher occurrence of acute kidney injury during hospitalization than the low‐U‐NGAL group (P=0.0012). Kaplan‐Meier analysis revealed that the high‐U‐NGAL group exhibited a worse prognosis than the low‐U‐NGAL group in all‐cause death (hazard ratio 2.07; 95%CI 1.38‐3.12, P=0.0004), cardiovascular death (hazard ratio 2.29; 95%CI 1.28‐4.24, P=0.0052), and heart failure admission (hazard ratio 1.77; 95%CI 1.13‐2.77, P=0.0119). The addition of U‐NGAL to the estimated glomerular filtration rate significantly improved the predictive accuracy of all‐cause mortality (P=0.0083). ConclusionsIn acute decompensated heart failure patients, an elevated U‐NGAL level on the first day of admission was related to the development of clinical acute kidney injury and independently associated with poor prognosis.

BACKGROUND:Low-dose aspirin is widely recommended for patients at high risk for cardiovascular disease (CVD); however, it remains uncertain whether long-term treatment adversely affects renal function in patients with diabetes. We investigated whether long-term low-dose aspirin affects renal dysfunction in patients with diabetes. METHODS:We conducted a randomized controlled trial (RCT), the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, to evaluate low-dose aspirin as primary prevention for CVD in patients with type 2 diabetes. We followed the patients with negative urine dipstick albumin of the JPAD trial in a cohort study after the RCT period was completed. Patients were randomly allocated to receive aspirin (81 mg or 100 mg daily, aspirin group) or no aspirin (no aspirin group). After the RCT, the treating physician decided whether to administer aspirin. We evaluated the incidence of positive urine dipstick albumin and annual changes in estimated glomerular filtration rate (eGFR). RESULTS:Positive urine dipstick albumin developed in 297 patients in the aspirin group (n = 1,075) and 270 patients in the no aspirin group (n = 1,098) during follow-up (median, 8.5 years). Intention-to-treat analysis showed low-dose aspirin did not increase the incidence of positive urine dipstick albumin (hazard ratio [HR], 1.17; 95% confidence interval [CI], 0.995-1.38). On-treatment analysis yielded similar results (HR, 1.08; 95% CI, 0.92-1.28). Multivariable analysis showed the incidence of positive urine dipstick albumin was higher among the elderly and those with elevated serum creatinine, high hemoglobin A1c, or high blood pressure; however, low-dose aspirin did not increase the risk of positive urine dipstick albumin. There were no significant differences in annual changes in eGFR between the groups (aspirin, -0.8 ± 2.9; no aspirin, -0.9 ± 2.5 ml/min/1.73 m(2)/year). CONCLUSION:Long-term low-dose aspirin does not affect eGFR and positive urine dipstick albumin in patients with type 2 diabetes.

Pancreatic ductal adenocarcinoma (PDAC) is difficult to distinguish from autoimmune pancreatitis (AIP) because of their clinical and radiological similarities, and therefore simple and minimally invasive surrogate markers for differential diagnosis would be useful. In our previous studies, we identified four microRNAs (miRNAs)-miR-7, miR-34a, miR-181d, and miR-193b -as MAPK-associated microRNAs whose expression was altered significantly with upregulation of the MAPK signaling pathway. Recently it has been reported that these miRNAs could be used as biomarkers in serum samples for accurate diagnosis of pancreatic lesions. The aim of the present study was to evaluate whether these MAPK-associated miRNAs in serum could be used as biomarkers for differentiating PDAC from AIP. We enrolled 69 patients with PDAC, 26 with intraductal papillary mucinous neoplasm (IPMN) and 15 with AIP. The expression of MAPK-associated miRNAs in serum was measured by quantitative real-time PCR. The 2-ΔCT method was used to quantify the expression of miRNAs, and the data were normalized using spiked-in synthetic cel-miR-39. Patients with PDAC or IPMN showed significantly higher amounts of serum MAPK-associated miRNAs than those with AIP (p

Danon disease, an X-linked dominant cardioskeletal myopathy, is caused by primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). To clarify the clinicopathological features and management, we performed the first nationwide, questionnaire-based survey on Danon disease in Japan. A total of 39 patients (17 males, 22 females) from 20 families were identified in the analysis. All patients had cardiomyopathy. Of the 21 patients who died, 20 (95%) died of cardiac failure or sudden cardiac arrest. Most patients had hypertrophic cardiomyopathy. Wolf⁻Parkinson⁻White syndrome was present at a comparatively high incidence (54% in males, 22% in females). Only one female patient received a heart transplant, which is the most effective therapy. Histopathologically, all male patients showed autophagic vacuoles with sarcolemmal features in muscle. Half of the probands showed de novo mutations. Male patients showed completely absent LAMP-2 expression in muscle. In contrast, female patients showed decreased LAMP-2 expression, which is suggested to reflect LAMP-2 haploinsufficiency due to a heterozygous null mutation. In conclusion, Danon disease is an extremely rare muscular disorder in Japan. Cardiomyopathy is the most significant prognostic factor and the main cause of death. Our findings suggest that the present survey can extend our understanding of the clinical features of this rare disease.

In May 2005 a 68-year-old woman received a VDD pacemaker implantation in the right pectoral region at our hospital for the treatment of complete atrioventricular block. In July 2008, she was diagnosed with dilated cardiomyopathy based on histological testing. In November 2008, she developed syncope due to ventricular tachycardia while at another hospital. She underwent external electrical cardioversion with an anterior-lateral paddle position using a single shock of 100 J. This shock led to severe bradycardia resulting in a transfer to our hospital. The physician who provided the shock could not have been aware that the patient had an implanted pacemaker. The skin above the pulse generator was burned. The electrocardiogram showed no pacing spikes or ventricular escape rhythm. Investigation of the pacemaker 3 hours after cardioversion revealed reprogramming of the device and a marked rise in the lead impedance (>3,000 ohm). Removal of the generator and implantation of a biventricular cardioverter defibrillator were required. The emergency situation, the small size of the generator, the small incision made using the buried suture method, and the patient's obesity all probably contributed to the physician's not noticing the implanted pacemaker. It is important to increase awareness of the severe consequences that may follow if the physician administering external defibrillation does not know about the patient's implanted pacemaker.

Tamoxifen (Tam) decreased the clearance of L-glutamate (L-Glu) by cultured astrocytes at 1 pM, 1 nM, and 1 μM, but became toxic at 10 μM. When L-Glu transporters were mostly inhibited by threo-β-benzyloxyaspartate (TBOA) (1 mM) or D,L-threo-β-hydroxyaspartate (THA) (1 mM), Tam (1 nM) did not change extracellular L-Glu concentration, confirming that Tam attenuates L-Glu transport through L-Glu transporters. ICI182,780, LY294002, and U0126 inhibited the effect of Tam dose-dependently, suggesting the involvement of estrogen receptors (ERs), the phosphatidylinositol 3-kinase (PI3K) cascade, and the mitogen-activated protein kinase (MAPK) cascade in the effect of Tam. Keywords:: tamoxifen, L-glutamate transporter, astrocyte

Neutrophil gelatinase-associated lipocalin (NGAL or LCN2) is an iron-transporting factor which possesses various activities such as amelioration of kidney injury and host defense against pathogens. Its circulating concentrations are elevated in acute and chronic kidney diseases and show a positive correlation with poor renal outcome and mortality, but its clinical significance in maintenance hemodialysis (HD) patients remains elusive.Serum NGAL levels were determined by enzyme-linked immunosorbent assay in out-patient, Japanese HD subjects. Their correlation to laboratory findings and morbidity (as development of severe infection or serum albumin reduction) was investigated using linear regression analysis and χ2 test.Pre-dialysis serum NGAL levels in HD patients were elevated by 13-fold compared to healthy subjects (n=8, P