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Myotonic dystrophy type-1 (DM1) is an autosomal dominant hereditary muscular dystrophy caused by CTG repeat expansions in the DMPK gene. Patients with DM1 suffer from progressive systemic myopathy and cardiomyopathy with life-threatening atrio-ventricular block. A mouse model of HSALR has been generally used for an animal model of DM1. However, this model mimics DM1 pathology by CTG repeat expansions in the ACTA1 gene (skeletal muscle actin, and is known to have no evident cardiomyopathy. Recently, hDMPK-77Tg mice have been established and expected to be an alternative animal model of DM1 because they have CTG repeat expansions in the DMPK gene. However, to date, cardiac phenotypes of hDMPK-77Tg mice are still unknown. We evaluated atrio-ventricular conduction of hDMPK-77Tg heterozygous mice at 14-15 weeks of age (n=2) and compared them to the age-matched control B6-wildtype mice (n=4). The PR interval was measured on the automatically generated electrocardiogram fusion waveform from 10 consecutive beats at the timing of 450 bpm of heart rate under 1-4 % isoflurane anesthesia. PR intervals of B6-wildtype and hDMPK77-Tg mice were 47.04 ± 10.42 and 56.67 ± 9.89 ms, respectively. Although the difference was not statistically significant due to the limited number of animals, a trend toward prolonged PR interval in hDMPK77-Tg mice was observed. Our preliminary study suggests that hDMPK77-Tg mice can be an animal model of DM1 cardiomyopathy with atrio-ventricular conduction disorder. [ABSTRACT FROM AUTHOR]

We herein report a patient with herpes zoster (HZ), severe hyponatremia, and hypokalemia. Syndrome of inappropriate antidiuresis (SIAD) leads to euvolemic hyponatremia and hypoosmotic plasma due to inadequate diuresis. Hyponatremia in the current patient was caused by SIAD and associated with HZ of the trigeminal facial nerve (V1). The patient also had hypokalemia, with excessive urinary potassium excretion and elevated cortisol levels. Hypokalemia is caused by hypercortisolemia, which is stimulated by HZ pain. Adequate treatment for HZ and comprehensive pain control play pivotal roles in improving SIAD, cortisol hypersecretion, and the subsequent electrolyte abnormalities.

Post-induction hypotension (PIH) during general anesthesia is a serious concern due to its high incidence and association with adverse postoperative outcomes and prognosis. We prospectively enrolled consecutive 1,603 patients scheduled for non-cardiac and cardiac surgery under general anesthesia. The primary outcome was defined as the lowest mean blood pressure from induction of general anesthesia to the start of surgery: post-induction blood pressure (PIB). Multivariable regression analysis was used to investigate the relationships between PIB and preoperative echocardiographic measurements, types and doses of anesthetic agents, and preoperative comorbidities and oral medication. Left ventricle regional wall motion abnormality (RWMA) and lower estimated glomerular filtration rate significantly associated lower PIB. Factors significantly associated with higher PIB were high BMI, beta blockers, high pre-induction mean blood pressure, and starting induction in the afternoon. Sevoflurane and prophylactic norepinephrine use were associated with higher PIB as anesthetic interventions. Significant interactions were found between sevoflurane and RWMA (P for interaction: 0.01). This is the first study to demonstrate the feasibility of intervening in the selection of anesthetic agents based on echocardiographic findings and to recommend the use of sevoflurane and prophylactic norepinephrine for the prevention of PIH, especially in patients with RWMA., (© 2024. The Author(s).)

A 60-year-old woman with a recent history of presumed cardiogenic cerebral infarction was referred for surgical removal of a left ventricular mass. She was diagnosed with Fabry disease eight years before. Transthoracic echocardiography showed a mobile echogenic mass in the left ventricular apex. Emergency surgery was carried out to prevent the recurrence of embolism. On cardiopulmonary bypass, the left ventricle was opened in its apical portion and a pedunculated mass was removed from the left ventricular wall. Direct suturing closure followed. The mass was histologically a thrombus composed mainly of erythrocytes and fibrin, without a tumor component. The patient was put on a standard "heparin taken over by warfarin" anticoagulation regimen. The postoperative course was clinically uneventful, but immediate transthoracic echocardiography showed an immobile thrombus on the left ventricular suture line. The patient was followed up with intensified anticoagulation and additional antiplatelet therapy. At 7 months after surgery, the patient had not experienced recurrence of embolism. Early thrombogenesis at the surgical site against anticoagulation may feature the highly thrombogenic status in Fabry disease. Therefore, early and strong warfarinization with antiplatelet therapy may be recommended for patients who undergo cardiotomy with this pathology., Learning Objective: Fabry disease accelerates thrombogenesis in blood vessels but does so uncertainly in the cardiac chambers. We describe a patient who developed cerebral infarction from left ventricular thrombosis. After a successful surgical removal of the thrombus from the left ventricle, a new thrombus recurred over the ventricular suture line against a diligent but standard anticoagulation regimen., Competing Interests: The authors declare no conflicts of interest associated with this manuscript., (© 2024 Japanese College of Cardiology. Published by Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Age-related changes in left ventricular (LV) structure and function lower the threshold for the onset of heart failure with preserved ejection fraction (HFpEF). LV parameters change also with race; however, the racial differences in age-related changes in LV parameters with and without adjustment for body mass index (BMI), heart rate (HR), and blood pressure (BP) remain unclear., Methods and Results: We performed a subanalysis of the World Alliance Society of Echocardiography Normal Values Study, an international cross-sectional study that examined normal echocardiographic values in 15 countries. The age-related changes in 2-dimensional echocardiographic derived parameters including LV size, systolic function, and mass, were compared between healthy Japanese (n=227) and healthy White (n=98) and Black (n=69) American participants. In men, age-related changes in all parameters did not differ significantly among races. However, compared with Japanese women, White American women had a smaller body surface area (BSA)-indexed LV volume, BSA-indexed LV internal dimension at end-systole, BSA-indexed LV stroke volume, and LV mass index to BSA, and a larger LV ejection fraction with age, even after adjusting for BMI, HR, and BP., Conclusions: Age-related changes in LV structure and function, which are important for the pathophysiology of HFpEF, may differ by race. Therefore, future studies examining echocardiographic reference values for each age group in each race are needed.

The generalization of deep neural network algorithms to a broader population is an important challenge in the medical field. We aimed to apply self-supervised learning using masked autoencoders (MAEs) to improve the performance of the 12-lead electrocardiography (ECG) analysis model using limited ECG data. We pretrained Vision Transformer (ViT) models by reconstructing the masked ECG data with MAE. We fine-tuned this MAE-based ECG pretrained model on ECG-echocardiography data from The University of Tokyo Hospital (UTokyo) for the detection of left ventricular systolic dysfunction (LVSD), and then evaluated it using multi-center external validation data from seven institutions, employing the area under the receiver operating characteristic curve (AUROC) for assessment. We included 38,245 ECG-echocardiography pairs from UTokyo and 229,439 pairs from all institutions. The performances of MAE-based ECG models pretrained using ECG data from UTokyo were significantly higher than that of other Deep Neural Network models across all external validation cohorts (AUROC, 0.913-0.962 for LVSD, p < 0.001). Moreover, we also found improvements for the MAE-based ECG analysis model depending on the model capacity and the amount of training data. Additionally, the MAE-based ECG analysis model maintained high performance even on the ECG benchmark dataset (PTB-XL). Our proposed method developed high performance MAE-based ECG analysis models using limited ECG data., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sawano et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Downhill esophageal varices often develop because of venous hypertension caused by either superior vena cava obstruction or compression. We herein present a case of downhill esophageal varices caused by a giant goiter in a patient with postoperative Graves' disease. A 66-year-old man presented with an enlarged goiter. Gastrointestinal endoscopy revealed upper esophageal varices. This patient was successfully treated with repeated segmental embolization of the thyroid arteries that fed the goiter, followed by embolization of the inflow vein for downhill esophageal varices. Three years later, no re-enlargement of either the goiter or the appearance of downhill varices was observed. Segmental embolization therapy is thus considered to be a safe alternative for the treatment of downhill esophageal varices caused by giant goiter.

This study aims to develop a new heart failure with preserved ejection fraction (HFpEF) diagnostic algorithm tailored to Asian populations, addressing limitations of current diagnostic models. Existing HFpEF diagnostic algorithms primarily target patients with dyspnea and metabolic comorbidities, such as obesity, which are more prevalent in Western populations. However, in Asian countries, HFpEF cases are less frequently associated with obesity, leading to less prominent dyspnea and more noticeable symptoms such as fatigue. By incorporating exercise stress echocardiography and focusing on early-stage HFpEF, particularly in patients with symptoms beyond dyspnea, we seek to enable early diagnosis and intervention, ultimately extending healthy life expectancy and improving quality of life. The STOP-HFPEF (The Multicenter STudy On a Precise algorithm for diagnosis of Heart Failure with Preserved Ejection Fraction) study is a multicenter prospective observational investigation in Japan. Certified by the Japanese Society of Echocardiography, the study includes participants aged 20 and older who undergo exercise stress echocardiography. The primary goal is to develop a scoring model for diagnosing HFpEF in heart-failure stages A, B, and C. Secondary outcomes will assess the clinical utility of the new diagnostic score by comparing heart-failure incidence, cardiovascular events, and mortality rates.Study registration: Registered at the UMIN registry (UMIN000054565) on 1 July 2024., (© 2024. Japanese Society of Echocardiography.)

Competing Interests: Conflict of interest: None declared.

Background: Convolutional neural networks (CNNs) have emerged as a novel method for evaluating heart failure (HF) in adult electrocardiograms (ECGs). However, such CNNs are not applicable to pediatric HF, where abnormal anatomy of congenital heart defects plays an important role. ECG-based CNNs reflecting neurohormonal activation (NHA) may be a useful marker of pediatric HF. This study aimed to develop and validate an ECG-derived marker of pediatric HF that reflects the risk of future cardiovascular events., Methods: Based on 21,378 ECGs from 8324 children, a CNN was trained using B-type natriuretic peptide (BNP) and the occurrence of major adverse cardiovascular events (MACEs). The output of the model, or the electrical heart failure indicator (EHFI), was compared with the BNP regarding its ability to predict MACEs in 813 ECGs from 295 children., Results: EHFI achieved a better area under the curve than BNP in predicting MACEs within 180 days (0.826 versus 0.691, p = 0.03). On Cox univariable analyses, both EHFI and BNP were significantly associated with MACE (log10 EHFI: hazard ratio [HR] = 16.5, p < 0.005 and log10 BNP: HR = 4.4, p < 0.005). The time-dependent average precisions of EHFI in predicting MACEs were 32.4%-67.9% and 1.6-7.5-fold higher than those of BNP in the early period. Additionally, the MACE rate increased monotonically with EHFI, whereas the rate peaked at approximately 100 pg/mL of BNP and decreased in the higher range., Conclusions: ECG-derived CNN is a novel marker of HF with different prognostic potential from BNP. CNN-based ECG analysis may provide a new guide for assessing pediatric HF., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Gastric conduit necrosis (GCN) after esophagectomy is a serious complication that can prove fatal. Herein, we report a rare case of GCN with a severe course that improved with conservative treatment., Case Presentation: We present the case of a 78-year-old male patient who underwent an Ivor Lewis esophagectomy and developed a massive GCN. The patient was critically ill in the initial phase but recovered quickly; he also had a ruptured gallbladder and a bleeding jejunal ulcer. On the 22nd postoperative day, massive GCN was revealed on endoscopy. Considering the recovery course, careful observation with a decompressing nasal gastric tube was the treatment of choice. The GCN was managed successfully, having been completely replaced by fine mucosa within 9 months postoperatively. The patient completed his follow-up visit 5 years after surgery without any evident disease recurrence. Five and a half years after the surgery, the patient presented with progressive weakness and deterioration of renal function. Gastrointestinal endoscopy revealed a large ulcer at the anastomotic site. Three months later, computed tomography revealed a markedly thin esophageal wall, accompanied by adjacent lung consolidation. An esophagopulmonary fistula was diagnosed; surgery was not considered, owing to the patient's age and markedly deteriorating performance status. He died 2013 days after the diagnosis., Conclusions: Massive GCN after esophagectomy often requires emergency surgery to remove the necrotic conduit. However, this report suggests that a conservative approach can save lives and preserve the gastric conduit in these cases, thereby augmenting the quality of life., (© 2024. The Author(s).)

Cardiac discomfort has been reported periodically in COVID-19-vaccinated individuals. Thus, this study aimed to evaluate the role of myocardial strains in the early assessment of the clinical presentations after COVID-19 vaccination. Totally, 121 subjects who received at least one dose of vaccine within 6 weeks underwent laboratory tests, electrocardiogram (ECG), and echocardiogram. Two-dimensional speckle tracking echocardiography (2D-STE) was implemented to analyze changes in the left ventricular myocardium. After vaccination, 66 individuals (55.4 ± 17.4 years) developed cardiac discomforts, such as chest tightness, palpitations, dyspnea, and chest pain. The ECG readings exhibited both premature ventricular contractions and premature atrial contractions (n = 24, 36.4%), while none of the individuals in the control group manifested signs of cardiac arrhythmia. All had normal serum levels of creatine phosphokinase, creatine kinase myocardial band, troponin, N-terminal pro b-type natriuretic peptide, platelets, and D-dimer. Left ventricular ejection fraction in the symptomatic group (71.41% ± 7.12%) and the control group (72.18% ± 5.11%) (p = 0.492) were normal. Use of 2D-STE presented global longitudinal strain (GLS) and global circumferential strain (GCS) was reduced in the symptomatic group (17.86% ± 3.22% and 18.37% ± 5.22%) compared to the control group (19.54% ± 2.18% and 20.73% ± 4.09%) (p = 0.001 and p = 0.028). COVID-19 vaccine-related cardiac adverse effects can be assessed early by 2D-STE. The prognostic implications of GLS and GCS enable the evaluation of subtle changes in myocardial function after vaccination., (© 2024. The Author(s).)

Background: Emerging evidence suggests a pathophysiological link between obesity and atrial fibrillation (AF). However, the contribution of body fat distribution to left atrial (LA) remodeling and its reversibility remain unclear in nonobese AF patients., Objectives: The purpose of this study was to investigate the association of body fat distribution with LA size and reverse remodeling (LARR)., Methods: In total, 116 nonobese patients with AF (88 men, age 63 ± 11 years) who underwent first catheter ablation (CA) were included. Body fat distribution was assessed with bioelectrical impedance, and body fat percentage (BF%) and central fat percentage (CF%) were calculated. Patients were categorized by body size metrics (body mass index [BMI] and waist-to-hip [W/H] ratio) and fat parameters (BF% and CF%). Echocardiography was performed before and 6 months after CA. Multivariable logistic regression was used to examine the association between the 4 metrics (ie, BMI, W/H ratio, BF%, and CF%) and a lack of LARR (<15% reduction or increase in the LA volume index)., Results: Body size metrics and adiposity measures were not independently associated with baseline LA size. Six months after CA, the higher W/H ratio and CF% groups exhibited persistent LA enlargement compared to their counterparts (both P  < 0.01). In the multivariable analysis, W/H ratio and CF% were associated with a lack of LARR (adjusted ORs of 3.86 and 2.81 per 0.10 and 10% increase, respectively, both P  < 0.01). The combined assessment of CF% with W/H ratio provided complementary risk stratification for persistent LA enlargement., Conclusions: Central adiposity was associated with a lack of LARR after CA, highlighting the importance of assessing body fat distribution even in nonobese patients., Competing Interests: This work was supported in part by 10.13039/100018736Kaken 22K12859. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Coronary artery bypass grafting (CABG) using the right gastroepiploic artery (RGEA) is a well-established, safe procedure. However, problems with RGEA grafts in subsequent abdominal surgeries can lead to fatal complications. This report presents the first case of right hepatectomy for hepatocellular carcinoma after CABG using the RGEA., Case Presentation: We describe a case in which a right hepatectomy for an 81-year-old male patient with hepatocellular carcinoma was safely performed after CABG using a RGEA graft. Preoperatively, three-dimensional computed tomography (3D- CT) images were constructed to confirm the run of the RGEA graft. The operation was conducted with the standby of a cardiovascular surgeon if there was a problem with the RGEA graft. The RGEA graft had formed adhesions with the hepatic falciform ligament, necessitating meticulous dissection. After the right hepatectomy, the left hepatic lobe descended into the vacated space, exerting traction on the RGEA. However, this traction was mitigated by suturing the hepatic falciform ligament to the abdominal wall, ensuring stability of the RGEA. There were no intraoperative or postoperative complications., Conclusion: It is crucial to confirm the functionality and anatomy of the RGEA graft preoperatively, handle it gently intraoperatively, and collaborate with cardiovascular surgeons., (© 2024. The Author(s).)

We describe a technique to repair ischemic ventricular septal rupture via a left ventriculotomy. It employs a large endoventricular patch as a "lining" over the locally patched septal defect and the free wall defect which is going to be roofed with an external patch. Both defects are then closed in double layers, holding a single continuous patch. The technique enhances the advantage of the left ventriculotomy in the repair and minimizes ventriculotomy-related morbidity., (© 2023. The Author(s).)

Background: Atrial fibrillation (AF) progression is closely related to heart failure occurrence, and catheter ablation carries a beneficial effect for heart failure prevention. Recently, particular attention has been given to left atrial (LA) function and functional reserve in the pathogenesis linking AF and heart failure, although its significance and reversibility is not well studied., Methods and Results: We prospectively investigated 164 patients with AF with normal left ventricular systolic function and free from heart failure who underwent first catheter ablation and pre-/postprocedural echocardiography. Conventional and speckle-tracking echocardiography were performed at rest and during passive leg lifting to assess LA size, LA reservoir strain (LARS), and functional reserve calculated as passive leg lifting-LARS - rest-LARS. Patients were categorized into 3 AF subtypes: paroxysmal AF (N=95), persistent AF (PeAF; N=50), and long-standing persistent AF (LS-PeAF; N=19). The PeAF and LS-PeAF groups had larger LA size and reduced LARS compared with the paroxysmal AF group (all P <0.05). LA functional reserve was significantly impaired in the LS-PeAF group ( P =0.003). In multivariable analysis, LS-PeAF and advanced age were significantly associated with impaired LA functional reserve. Among 149 patients with sinus rhythm 1 to 2 days after catheter ablation, LARS was significantly improved in both PeAF and LS-PeAF groups but was still lower than that in the paroxysmal AF group. Sinus rhythm restoration also led to amelioration of LA functional reserve in patients with LS-PeAF., Conclusions: AF progression was related to impaired LARS and LA functional reserve, and restoration of sinus rhythm might contribute to early LA reverse remodeling.

The tricuspid annulus (TA) is the primary target of tricuspid valve (TV) surgery for tricuspid regurgitation (TR). However, the reference values for TA geometry in the Japanese population is currently unavailable. We aimed to elucidate the geometric reference values of the TA in Japanese individuals using 3-dimensional (3D) echocardiography.We conducted a prospective study using transthoracic 3D echocardiography on 142 healthy Japanese subjects aged between 20 and 79 years. The tricuspid geometric parameters in the late-diastole and the mid-systole were analyzed using custom 3D software (Realview™).After excluding 46 subjects with poor images, data from 96 subjects (67.6%) were analyzed. TA area and circumference showed strong correlations with body surface area (BSA) (P < 0.001 for all), while some of these parameters exhibited weak correlations with age. Gender differences in TV geometry were assessed across 3 age groups: 20-39 years (42 subjects), 40-59 years (28 subjects), and 60-79 years (26 subjects). In the youngest subjects (20-39 years), males had a significantly larger TA area and smaller anterior-posterior and medial-lateral diameters (P < 0.001 for all), even after adjusting for BSA, indicating gender differences of TA geometry. These differences diminished with age.We present reference values for TA geometry by age and gender in a Japanese cohort. BSA may be a suitable metric for indexing the TA parameters. While age-related changes in TA parameters may not be significant, gender differences, particularly in younger individuals, persist even after adjusting for BSA.

Duchenne muscular dystrophy (DMD) is an intractable X-linked myopathy caused by dystrophin gene mutations. Patients with DMD suffer from progressive muscle weakness, inevitable cardiomyopathy, increased heart rate (HR), and decreased blood pressure (BP). The aim of this study was to clarify the efficacy and tolerability of ivabradine treatment for DMD cardiomyopathy.A retrospective analysis was performed in 11 patients with DMD, who received ivabradine treatment for more than 1 year. Clinical results were analyzed before (baseline), 6 months after, and 12 months after the ivabradine administration.The initial ivabradine dose was 2.0 ± 1.2 mg/day and the final dose was 5.6 ± 4.0 mg/day. The baseline BP was 95/64 mmHg. A non-significant BP decrease to 90/57 mmHg was observed at 1 month but it recovered to 97/62 mmHg at 12 months after ivabradine administration. The baseline HR was 93 ± 6 bpm and it decreased to 74 ± 12 bpm at 6 months (P = 0.011), and to 77 ± 10 bpm at 12 months (P = 0.008). A linear correlation (y = 2.2x + 5.1) was also observed between the ivabradine dose (x mg/day) and HR decrease (y bpm). The baseline LVEF was 38 ± 12% and it significantly increased to 42 ± 9% at 6 months (P = 0.011) and to 41 ± 11% at 12 months (P = 0.038). Only 1 patient with the lowest BMI of 11.0 kg/m 2 and BP of 79/58 mmHg discontinued ivabradine treatment at 6 months, while 1-year administration was well-tolerated in the other 10 patients.Ivabradine decreased HR and increased LVEF without lowering BP, suggesting it can be a treatment option for DMD cardiomyopathy.

Background: Left heart abnormalities are risk factors for heart failure. However, echocardiography is not always available. Electrocardiograms (ECGs), which are now available from wearable devices, have the potential to detect these abnormalities. Nevertheless, whether a model can detect left heart abnormalities from single Lead I ECG data remains unclear., Methods and results: We developed Lead I ECG models to detect low ejection fraction (EF), wall motion abnormality, left ventricular hypertrophy (LVH), left ventricular dilatation, and left atrial dilatation. We used a dataset comprising 229,439 paired sets of ECG and echocardiography data from 8 facilities, and validated the model using external verification with data from 2 facilities. The area under the receiver operating characteristic curves of our model was 0.913 for low EF, 0.832 for wall motion abnormality, 0.797 for LVH, 0.838 for left ventricular dilatation, and 0.802 for left atrial dilatation. In interpretation tests with 12 cardiologists, the accuracy of the model was 78.3% for low EF and 68.3% for LVH. Compared with cardiologists who read the 12-lead ECGs, the model's performance was superior for LVH and similar for low EF., Conclusions: From a multicenter study dataset, we developed models to predict left heart abnormalities using Lead I on the ECG. The Lead I ECG models show superior or equivalent performance to cardiologists using 12-lead ECGs.

Bronchogenic cysts are congenital malformations of the bronchial tree, detected as a cystic and/or mass lesion in the thoracic cavity. Although it occurs in distant locations, such as skin and retroperitoneum, to the best of our knowledge, little is known about the components and phenotypes of the epithelium that line a bronchogenic cyst in rare sites. The present study reviewed 34 bronchogenic cysts that were surgically resected at Osaka Medical and Pharmaceutical University Hospital (Osaka, Japan) from January 1998 to December 2020. Bronchogenic cysts in rare sites were detected and diagnosis was confirmed based on the presence of pseudostratified, ciliated and/or columnar epithelium together with at least one of the following: Cartilage, smooth muscle or seromucous glands. The phenotypes of epithelium lining the cyst were characterized using immunohistochemical analysis. A total of six bronchogenic cysts in rare sites (two cases each in the retroperitoneum and skin and one case each in the cervical spinal cord and pericardial cavity) met the criteria for confirmation of the diagnoses. The epithelium lining the cyst stained positive for cytokeratin CK7 and thyroid transcription factor 1 (a marker expressed in thyroid follicles and bronchial epithelium) and negative for CK20, indicating that the phenotypes were similar to those of the respiratory epithelium. The present study demonstrated that a bronchogenic cyst can occur in rare sites, such as the retroperitoneum, skin, spinal cord and pericardial cavity, suggesting that it should be considered as a differential diagnosis before surgical approach to implement relevant management modalities such as follow-up, simple or radical resection., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Onishi et al.)

Growth differentiation factor-15 (GDF15) is a stress-activated cytokine that regulates cell growth and inflammatory and stress responses. We previously reported the role and regulation of GDF15 in pituitary corticotrophs. Dexamethasone increases Gdf15 gene expression levels and production. GDF15 suppresses adrenocorticotropic hormone synthesis in pituitary corticotrophs and subsequently mediates the negative feedback effect of glucocorticoids. Here, we analyzed corticotropin-releasing factor (Crf) promoter activity in hypothalamic 4B cells transfected with promoter-driven luciferase reporter constructs. The effects of time and GDF15 concentration on Crf mRNA levels were analyzed using quantitative real-time polymerase chain reaction. Glial cell-derived neurotrophic factor family receptor α-like (GFRAL) protein is expressed in 4B cells. GDF15 increased Crf promoter activity and Crf mRNA levels in 4B cells. The protein kinase A and C pathways also contributed to the GDF15-induced increase in Crf gene expression. GDF15 stimulates GFRAL, subsequently increasing the phosphorylation of AKT, an extracellular signal-related kinase, and the cAMP response element-binding protein. Therefore, GDF15-dependent pathways may be involved in regulating Crf expression under stressful conditions in hypothalamic cells., Competing Interests: Declarations of interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Although accurate assessment of right ventricular (RV) morphology and function is clinically important, data regarding reference values for echocardiographic measurements of the right ventricle in the Japanese population are limited. Methods and Results: The World Alliance Society of Echocardiography (WASE) Normal Values Study was conducted to examine normal echocardiographic values in 15 countries. Using the WASE study database, we analyzed 2-dimensional echocardiographic parameters of RV size and systolic function in 192 healthy Japanese individuals and compared them with those obtained from 153 healthy American individuals. In the Japanese population, the absolute values of RV dimensions were smaller for women than men, although the difference disappeared after the data were adjusted for body surface area. RV dimensions, RV length and RV area were smaller in the elderly, but age did not affect RV systolic function. The absolute value, but not the adjusted value, of RV size tended to be smaller in Japanese than American individuals for both sexes. For men, RV systolic function parameters were lower in the Japanese population. This trend was not seen in women. Conclusions: The present study identified normal reference values for RV size and systolic function in a healthy Japanese population. Sex, age, and race had a significant impact on RV size; however, this trend was weak for RV systolic function., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2023, THE JAPANESE CIRCULATION SOCIETY.)

Aims: Emerging evidence suggests an association between non-alcoholic fatty liver disease (NAFLD) and heart failure (HF). We investigated the relationship between NAFLD and left ventricular (LV) functional remodelling in a general population sample without overt cardiac and liver disease., Methods and Results: We included 481 individuals without significant alcohol consumption who voluntarily underwent an extensive cardiovascular health check. The fatty liver index (FLI) was calculated for each participant, and NAFLD was defined as FLI ≥ 60. All participants underwent 2D transthoracic echocardiography; LV global longitudinal strain (LVGLS) was assessed with speckle-tracking analysis. Univariable and multivariable linear regression models were constructed to investigate the possible association between NAFLD and LVGLS. Seventy-one (14.8%) participants were diagnosed with NAFLD. Individuals with NAFLD exhibited larger LV size and LV mass index than those without NAFLD, although left atrial size and E / e ' ratio did not differ between groups. Left ventricular global longitudinal strain was significantly reduced in participants with vs. without NAFLD (17.1% ± 2.4% vs. 19.5% ± 3.1%, respectively; P < 0.001). The NAFLD group had a significantly higher frequency of abnormal LVGLS (<16%) than the non-NAFLD group (31.0% vs. 10.7%, respectively; P < 0.001). Multivariable linear regression analysis demonstrated that higher FLI score was significantly associated with impaired LVGLS independent of age, sex, conventional cardiovascular risk factors, and echocardiographic parameters (standardized β -0.11, P = 0.031)., Conclusion: In the general population without overt cardiac and liver disease, the presence of NAFLD was significantly associated with subclinical LV dysfunction, which may partly explain the elevated risk of HF in individuals with NAFLD., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background Elevated left atrial (LA) pressure predisposes individuals to the initiation and persistence of atrial fibrillation (AF), and LA hypertension is associated with AF recurrence after catheter ablation (CA). However, the exact frequency and factors associated with LA hypertension are unknown, and its noninvasive estimation is challenging. This study aimed to investigate the prevalence and determinants of LA hypertension in patients with AF who underwent first CA. Methods and Results We examined 183 patients with AF who underwent conventional and speckle-tracking echocardiography before CA to assess LA size, reservoir strain, and stiffness. Direct LA pressure was measured at the time of CA, and LA hypertension was defined as mean LA pressure >15 mm Hg. Thirty-three (18.0%) patients exhibited LA hypertension. Patients with LA hypertension had a significantly larger LA volume index (40.2 [28.4-52.1] versus 34.1 [26.9-42.4] mL/m 2 , P =0.025), reduced LA reservoir strain (15.1 [10.4-21.7] versus 22.7 [14.4-32.3] %, P =0.002) and increased LA stiffness (0.69 [0.34-0.99] versus 0.36 [0.24-0.54], P <0.001). Multivariable analyses showed that waist circumference, C-reactive protein level, LA reservoir strain, and LA stiffness were independently associated with LA hypertension (all P <0.05), while LA volume and E/e' ratio were not. Among echocardiographic parameters, receiver operating characteristic curve analysis identified LA stiffness as the best predictor of LA hypertension. Conclusions Approximately 20% of patients with AF who underwent CA had LA hypertension. Central obesity and inflammation might be involved in the pathophysiological mechanisms of LA hypertension, and echocardiography-derived LA stiffness may have clinical utility for the detection of LA hypertension before CA.

Background: Normal values for three-dimensional (3D) right ventricular (RV) size and function are not well established, as they originate from small studies that involved predominantly white North American and European populations, did not use RV-focused views, and relied on older 3D RV analysis software. The World Alliance Societies of Echocardiography study was designed to generate reference ranges for normal subjects around the world. The aim of this study was to assess the worldwide capability of 3D imaging of the right ventricle and report size and function measurements, including their dependency on age, sex, and ethnicity., Methods: Healthy subjects free of cardiac, pulmonary, and renal disease were prospectively enrolled at 19 centers in 15 countries, representing six continents. Three-dimensional wide-angle RV data sets were obtained and analyzed using dedicated RV software (TomTec) to measure end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume, and ejection fraction (EF). Results were categorized by sex, age (18-40, 41-65, and >65 years) and ethnicity., Results: Of the 2,007 subjects with attempted 3D RV acquisitions, 1,051 had adequate image quality for confident measurements. Upper and lower limits for body surface area-indexed EDV, ESV, and EF were 48 and 95 mL/m 2 , 19 and 43 mL/m 2 , and 44% and 58%, respectively, for men and 42 and 81 mL/m 2 , 16 and 36 mL/m 2 , and 46% and 61%, respectively, for women. Men had significantly larger EDVs, ESVs, and stroke volumes (even after body surface area indexing) and lower EFs than women (P < .05). EDV and ESV did not show any meaningful differences among age groups. Three-dimensional RV volumes were smallest in Asians., Conclusions: Reliability of 3D RV acquisition is low worldwide, underscoring the importance of future improvements in imaging techniques. Sex and race must be taken into consideration in the assessment of both RV volumes and EF., (Copyright © 2023 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Objectives: Diabetes frequently results in cognitive impairment, but it is less clear if brain health is adversely affected during the prediabetic stage. Our aim is to identify possible changes in brain volume as measured by magnetic resonance imaging (MRI) in a large elderly population stratified according to level of "dysglycemia.", Methods: This is a cross-sectional study of 2144 participants (median age 69 years, 60.9% female) who underwent 3-T brain MRI. Participants were divided into 4 dysglycemia groups based on HbA1c levels (%): normal glucose metabolism (NGM) (< 5.7%), prediabetes (5.7 to < 6.5%), undiagnosed diabetes (6.5% or higher), and known diabetes (defined by self-report)., Results: Of the 2144 participants, 982 had NGM, 845 prediabetes, 61 undiagnosed diabetes, and 256 known diabetes. After adjustment for age, sex, education, body weight, cognitive status, smoking, drinking, and disease history, total gray matter volume was significantly lower among participants with prediabetes (0.41% lower, standardized β =  - 0.0021 [95% CI - 0.0039, - 0.00039], p = 0.016), undiagnosed diabetes (1.4% lower, standardized β =  - 0.0069 [95% CI - 0.012, - 0.002], p = 0.005), and known diabetes (1.1% lower, standardized β =  - 0.0055 [95% CI - 0.0081, - 0.0029], p < 0.001) compared to the NGM group. After adjustment, total white matter volume and hippocampal volume did not differ significantly between the NGM group and either the prediabetes group or the diabetes group., Conclusion: Sustained hyperglycemia may have deleterious effects on gray matter integrity even prior to the onset of clinical diabetes., Key Points: • Sustained hyperglycemia has deleterious effects on gray matter integrity even prior to the onset of clinical diabetes., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Cross sectionally measured, elevated arterial stiffness is associated with unfavorable left ventricular (LV) remodeling, suggesting its important role in the pathophysiology of heart failure. However, data linking the degree of arterial stiffness progression with LV remodeling are scarce., Objectives: The purpose of this study was to investigate the association between longitudinal change in arterial stiffness and changes in LV remodeling., Methods: Serial measurements of arterial stiffness by cardio-ankle vascular index (CAVI) were performed in 317 participants without cardiovascular disease and with normal arterial stiffness. LV size, mass, and function were assessed by transthoracic echocardiography and including LV global longitudinal strain (LVGLS) by speckle-tracking and tissue Doppler velocity (e') of the mitral annulus (diastolic function)., Results: During a median follow-up of 26.8 mo, there was a significant increase in CAVI ( P  < 0.001). Generalized estimating equation analyses showed that longitudinal increase in CAVI was associated with impaired LVGLS (estimate 0.46, 95% CI: 0.11-0.82; P  = 0.010) after adjustment for demographics and baseline cardiovascular factors, but not with changes of LV mass index and e' velocity. When controlling for longitudinal change of covariates, CAVI progression remained associated with change in LVGLS (estimate 0.50, 95% CI: 0.16-0.85; P  = 0.004). In sex stratified analysis, progression of CAVI was significantly associated with LVGLS deterioration only in women (estimate 0.92, 95% CI: 0.27-1.58; P  = 0.006)., Conclusions: Longitudinal increase in arterial stiffness is associated with deterioration in LVGLS. Vascular-ventricular coupling plays an important role in the progressive decline in ventricular function even at an early, subclinical stage., Competing Interests: This work was partially supported by 10.13039/501100003348Fukuda Foundation for Medical Technology. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Patients with secondary adrenal insufficiency can present with impaired free water excretion and hyponatremia, which is due to the enhanced secretion of vasopressin (AVP) despite increased total body water. AVP is produced in magnocellular neurons in the paraventricular nucleus of the hypothalamus (PVH) and supraoptic nucleus and in parvocellular corticotropin-releasing factor (CRF) neurons in the PVH. This study aimed to elucidate whether magnocellular AVP neurons or parvocellular CRF neurons coexpressing AVP are responsible for the pathogenesis of hyponatremia in secondary adrenal insufficiency. The number of CRF neurons expressing copeptin, an AVP gene product, was significantly higher in adrenalectomized AVP-floxed mice (AVPfl/fl) than in sham-operated controls. Adrenalectomized AVPfl/fl mice supplemented with aldosterone showed impaired water diuresis under ad libitum access to water or after acute water loading. They became hyponatremic after acute water loading, and it was revealed under such conditions that aquaporin-2 (AQP2) protein levels were increased in the kidney. Furthermore, translocation of AQP2 to the apical membrane was markedly enhanced in renal collecting duct epithelial cells. Remarkably, all these abnormalities observed in the mouse model for secondary adrenal insufficiency were ameliorated in CRF-AVP-/- mice that lacked AVP in CRF neurons. Our study demonstrates that CRF neurons in the PVH are responsible for the pathogenesis of impaired water excretion in secondary adrenal insufficiency., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Microvascular thrombosis is a typical symptom of COVID-19 and shows similarities to thrombosis. Using a microfluidic imaging flow cytometer, we measured the blood of 181 COVID-19 samples and 101 non-COVID-19 thrombosis samples, resulting in a total of 6.3 million bright-field images. We trained a convolutional neural network to distinguish single platelets, platelet aggregates, and white blood cells and performed classical image analysis for each subpopulation individually. Based on derived single-cell features for each population, we trained machine learning models for classification between COVID-19 and non-COVID-19 thrombosis, resulting in a patient testing accuracy of 75%. This result indicates that platelet formation differs between COVID-19 and non-COVID-19 thrombosis. All analysis steps were optimized for efficiency and implemented in an easy-to-use plugin for the image viewer napari, allowing the entire analysis to be performed within seconds on mid-range computers, which could be used for real-time diagnosis., (© 2023 The Authors. Cytometry Part A published by Wiley Periodicals LLC on behalf of International Society for Advancement of Cytometry.)

Primary aldosteronism (PA) is the most common cause of endocrine hypertension. Unilateral PA can be cured using unilateral adrenalectomy (Adx). PA surgery outcome (PASO) criteria, which include clinical and biochemical outcomes, have been proposed to evaluate PA cure after Adx. However, clinical outcomes are often inconsistent with biochemical outcomes. In addition, although confirmatory tests are included as endpoints of biochemical outcomes in the PASO criteria, their clinical usefulness has not yet been established. We evaluated clinical parameters and confirmatory test results before and after Adx in 16 patients with PA and assessed the usefulness of the confirmatory tests. The following were the clinical outcomes after Adx: 37.5% complete success, 62.5% partial success, and 0% absent success. The ratio of biochemical complete success was as follows: 69% aldosterone/renin ratio and basal plasma aldosterone concentration, 19% as assessed by the captopril challenge test, 47% as assessed by the saline infusion test, 30% as assessed by the furosemide upright test, and 100% urine aldosterone. Of these, biochemical complete success was judged in four cases by aldosterone/renin ratio and basal plasma aldosterone concentration, one case by captopril challenge test, five cases by saline infusion test, and one case by furosemide upright test. Although clinical outcomes and urine aldosterone levels improved after Adx, confirmatory tests failed to improve in some cases. The current criteria are not considered useful for biochemical evaluation after Adx. To determine whether additional treatment with mineralocorticoid receptor antagonists is required, more accurate biochemical criteria should be established after Adx., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2023 Shingo Murasawa et al.)

Aims: To investigate the exact prevalence of glucose metabolism disorders, and their impact on left atrial (LA) remodelling and reversibility in patients with atrial fibrillation (AF)., Methods and Results: We examined 204 consecutive patients with AF who underwent their first catheter ablation (CA). Oral glucose tolerance test was used to evaluate glucose metabolism disorders in 157 patients without known diabetes mellitus (DM). Echocardiography was performed before and 6 months after CA. Oral glucose tolerance test identified abnormal glucose metabolism in 86 patients [11 with newly diagnosed DM, 74 with impaired glucose tolerance (IGT) and 1 with impaired fasting glucose (IFG)]. Ultimately, 65.2% of patients had abnormal glucose metabolism. Diabetes mellitus group had the worst LA reservoir strain and LA stiffness (both P < 0.05), while there was no significant difference in baseline LA parameters between normal glucose tolerance (NGT) group and IGT/IFG group. The prevalence of LA reverse remodelling (≥15% decrease in the LA volume index at 6 months after CA) was significantly higher in NGT group compared with IGT/IFG and DM group (64.1 vs. 38.6 vs. 41.5%, P = 0.006). Both DM and IFG/IGT carry a significant risk of lack of LA reverse remodelling independent of baseline LA size and AF recurrence., Conclusion: Approximately 65% of patients with AF who underwent their first CA had abnormal glucose metabolism. Patients with DM had significantly impaired LA function compared with non-DM patients. Impaired glucose tolerance/IFG as well as DM carries significant risk of unfavourable LA reverse remodelling. Our observations may provide valuable information regarding the mechanisms and therapeutic strategies of glucose metabolism-related AF., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Although increased left ventricular (LV) mass is associated with adverse outcomes, measured values vary widely depending on the specific technique used. Moreover, the impact of sex, age, and race on LV mass remains controversial, further limiting the clinical use of this parameter. Accordingly, the authors studied LV mass using a variety of two-dimensional and three-dimensional echocardiographic techniques in a large population of normal subjects encompassing a wide range of ages., Methods: Transthoracic echocardiograms obtained from 1,854 healthy adult subjects (52% men) enrolled in the World Alliance Societies of Echocardiography (WASE) Normal Values Study, were divided into three age groups (young, 18-35 years; middle aged, 36-55 years; and old, >55 years). LV mass was obtained using five conventional techniques, including linear and two-dimensional methods, as well as direct three-dimensional measurement. All LV mass values were indexed to body surface area, and differences according to sex, age, and race were analyzed for each technique., Results: LV mass values differed significantly among the five techniques. Three-dimensional measurements were considerably smaller than those obtained using the other techniques and were closer to magnetic resonance imaging normal values reported in the literature. For all techniques, LV mass in men was significantly larger than in women, with and without body surface area indexing. These technique- and sex-related differences were larger than measurement variability. In women, age differences in LV mass were more pronounced and depicted significantly larger values in older age groups for all techniques, except three-dimensional echocardiography, which showed essentially no differences. LV mass was overall larger in black subjects than in white or Asian subjects., Conclusions: Significant differences in LV mass values exist across echocardiographic techniques, which are therefore not interchangeable. Sex-, race-, and age-related differences underscore the need for separate population specific normal values., (Copyright © 2022 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)