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We report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 ( BARD1) gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we established in tissue culture from a patient carrying the heterozygous BARD1 V523A mutation. We found that these cells had genomic instability, reduced DNA repair, and impaired apoptosis. Investigating the underlying signaling pathways, we found that BARD1 forms a trimeric protein complex with p53 and SERCA2 that regulates calcium signaling and apoptosis. We validated these findings in BARD1 -silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of BARD1 activity and revealed that heterozygous germline BARD1 mutations favor the development of mesothelioma and increase the susceptibility to asbestos carcinogenesis. These mesotheliomas are significantly less aggressive compared to mesotheliomas in asbestos workers., Competing Interests: Competing interests statement:M.C. has a patent issued for “Methods for Diagnosing a Predisposition to Develop Cancer.” M.C. and H.Y. have a patent issued for “Using Anti-HMGB1 Monoclonal Antibody or other HMGB1 Antibodies as a Novel Mesothelioma Therapeutic Strategy”, and a patent issued for “HMGB1 As a Biomarker for Asbestos Exposure and Mesothelioma Early Detection.” M.C. is a board-certified pathologist who provides consultation for pleural pathology, including medical-legal.

Functional mitral regurgitation (FMR) often coexists with atrial fibrillation (AF) and may have a causal relation with AF persistence and exacerbation of heart failure (HF). The purpose of this study was to investigate the impact of FMR on AF catheter ablation (AFCA) outcomes and improvement in FMR after AFCA in patients with HF with preserved ejection fraction (HFpEF) and nonparoxysmal AF. Excluding patients with primary valve disease or post-mitral valve repair, 280 patients with HFpEF who underwent CA for nonparoxysmal AF were retrospectively included. All patients completed 1-year follow-up and were assessed for FMR, AF recurrence and HF parameters, including echocardiography. At baseline, FMR was present in 153 (54.6%) patients (mild, n = 112; moderate, n = 40; severe, n = 1), and these were decreased to 70 (25%) significantly 1 year after AFCA (mild, n = 64; moderate, n = 6), 119 patients (78%) had improvement in MR (a decrease of ≥1 level in the severity from baseline to 1 year on echocardiography). Overall, 274 patients (97.9%) had sinus rhythm at the 1-year examination, and recurrent AF-free survival did not differ in patients with and without MR improvement (83.2% vs 82.4%, p = 0.908). However, the MR improvement group had a significantly lower cardiothoracic ratio, left atrial diameter, E/e', and B-type natriuretic peptide levels after 1 year than those in the MR nonimprovement group. In conclusion, the majority of the HFpEF patients with nonparoxysmal AF had improvement of FMR after AFCA with the high maintenance of sinus rhythm, leading to a virtuous cycle of cardiac function., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Clinical outcomes concerning the efficacy of excimer laser coronary angioplasty (ELCA) in real-world cases of acute myocardial infarction (MI) are limited. We evaluated and compared the impact of ELCA with manual aspiration thrombectomy on myocardial salvage and left ventricular (LV) systolic/diastolic function in patients with ST-segment elevation MI (STEMI) using nuclear scintigraphy.  We enrolled 143 consecutive patients with STEMI treated with ELCA (63 patients) or manual aspiration thrombectomy (80 patients) between September 2016 and December 2020 in a single-center hospital. We evaluated the peak creatine kinase (CK)/ creatine kinase-myocardial band (CK-MB) levels and performed single-photon emission computed tomography (SPECT) analyses with Quantitative Gated SPECT and Quantitative Perfusion SPECT (Auto QUANT 7.2) at 3-10 days using 123 I-BMIPP and 3 months following percutaneous coronary intervention using 99m Tc-tetrofosmin to evaluate myocardial salvage and LV systolic/diastolic function. No significant difference was observed in the patient and periprocedural characteristics. Peak CK-MB level was significantly different between the groups (ELCA group, 190.0 [70.5-342.0] IU/L vs. aspiration group, 256.5 [157.0-354.8] IU/L, p = 0.047). Although no significant difference was observed in myocardial salvage, significant improvement in the LV ejection fraction (14.1 [6.2-19.8]% vs. 9.5 [3.9-15.3]%, respectively, p = 0.018) and peak emptying rate (-0.54 [-1.02- (-0.27)] mL/s vs. -0.38 [-0.76- (-0.05)] mL/s, respectively, p = 0.017) were detected. ELCA could suppress the myocardial deviation enzymes and potentially improve systolic function compared to manual aspiration thrombectomy in patients with STEMI., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: Dynamic chest radiography allows for non-invasive cardiopulmonary blood flow assessment. However, data on its use for heart failure hemodynamic assessment are scarce. We utilized dynamic chest radiography to estimate heart failure hemodynamics., Method: Twenty heart failure patients (median age, 67 years; 17 men) underwent dynamic chest radiography and right heart catheterization. The analyzed images were 16-bit images (grayscale range: 0-65,535). Right atrial, right pulmonary artery, and left ventricular apex pixel values (average of the grayscale values of all pixels within a region of interest) were measured. The correlations of the minimum, maximum, mean, amount of change, and rate of change in pixel values with right atrial pressure, pulmonary artery pressure, pulmonary artery wedge pressure, and cardiac index were analyzed., Results: The mean right atrial pixel value and mean right atrial pressure (R = -0.576, P = 0.008), mean right pulmonary artery pixel value and mean pulmonary artery pressure (R = -0.546, P = 0.013), and left ventricular apex pixel value change rate and mean pulmonary artery wedge pressure (R = -0.664, P = 0.001) or cardiac index (R = 0.606, P = 0.005) were correlated. The left ventricular apex pixel value change rate identified low cardiac index (area under the curve, 0.792; 95% confidence interval, 0.590-0.993; P = 0.031) and low cardiac index with high pulmonary artery wedge pressure (area under the curve, 0.902; 95% confidence interval, 0.000-1.000; P = 0.030)., Conclusions: Dynamic chest radiography is a minimally invasive tool for heart failure hemodynamic assessment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: T. O. received research grants from Ono Pharmaceutical Co., Ltd., Bayer Pharmaceutical Co., Ltd., Daiichi-Sankyo Pharma Inc., and Amgen Astellas BioPharma K. K. outside of the submitted work. T. O. received honoraria from Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Medtronic Japan Co., Ltd. T. M. received lecture fees from Bayer Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Kowa Co., Ltd., MSD K. K., Mitsubishi Tanabe Pharma Co., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K. K., Pfizer Japan Inc., Sanofi-Aventis K. K., and Takeda Pharmaceutical Co., Ltd. T. M. received an unrestricted research grant from the Department of Cardiology, Nagoya University Graduate School of Medicine from Astellas Pharma Inc., Daiichi-Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Kowa Co., Ltd., MSD K. K., Mitsubishi Tanabe Pharma Co., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K. K., Otsuka Pharma Ltd., Pfizer Japan Inc., Sanofi-Aventis K. K., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

BAP1 is a powerful tumor suppressor gene characterized by haplo insufficiency. Individuals carrying germline BAP1 mutations often develop mesothelioma, an aggressive malignancy of the serosal layers covering the lungs, pericardium, and abdominal cavity. Intriguingly, mesotheliomas developing in carriers of germline BAP1 mutations are less aggressive, and these patients have significantly improved survival. We investigated the apparent paradox of a tumor suppressor gene that, when mutated, causes less aggressive mesotheliomas. We discovered that mesothelioma biopsies with biallelic BAP1 mutations showed loss of nuclear HIF-1α staining. We demonstrated that during hypoxia, BAP1 binds, deubiquitylates, and stabilizes HIF-1α, the master regulator of the hypoxia response and tumor cell invasion. Moreover, primary cells from individuals carrying germline BAP1 mutations and primary cells in which BAP1 was silenced using siRNA had reduced HIF-1α protein levels in hypoxia. Computational modeling and co-immunoprecipitation experiments revealed that mutations of BAP1 residues I675, F678, I679, and L691 -encompassing the C-terminal domain-nuclear localization signal- to A, abolished the interaction with HIF-1α. We found that BAP1 binds to the N-terminal region of HIF-1α, where HIF-1α binds DNA and dimerizes with HIF-1β forming the heterodimeric transactivating complex HIF. Our data identify BAP1 as a key positive regulator of HIF-1α in hypoxia. We propose that the significant reduction of HIF-1α activity in mesothelioma cells carrying biallelic BAP1 mutations, accompanied by the significant reduction of HIF-1α activity in hypoxic tissues containing germline BAP1 mutations, contributes to the reduced aggressiveness and improved survival of mesotheliomas developing in carriers of germline BAP1 mutations.

Background: The atrial defibrillation threshold (ADFT) for internal cardioversion is theoretically related to the critical mass for sustaining atrial fibrillation (AF)., Objective: This study aimed to investigate the association of ADFT for internal cardioversion with the outcome of catheter ablation for non-paroxysmal AF (non-PAF)., Methods: We included 368 consecutive patients who underwent first-time catheter ablation for non-PAF. Based on the degree of ADFT recorded by the internal cardioversion before pulmonary vein isolation, we divided the patients into low ADFT (<20 J) and high ADFT (≥20 J) groups and analysed the association between ADFT and atrial tachyarrhythmia recurrence., Results: There were 234 and 134 patients in the low and high ADFT groups, respectively. Of these, 39 patients (16.7%) and 41 (30.6%) patients, respectively, had atrial tachyarrhythmia recurrence during the 2.6±1.0 year follow-up. The high ADFT group showed a significantly higher atrial tachyarrhythmia recurrence than the low ADFT group (p=0.002). This finding was also noted in patients with long-standing persistent AF (p=0.032) but not in patients with persistent AF (p=0.159). The significant predictors of arrhythmia recurrence on multivariate analysis were high ADFT (p=0.004) and long-standing persistent AF (p=0.011). In multivariate analysis within the long-standing persistent AF group, only ADFT remained a significant risk factor for AF recurrence (p=0.035)., Conclusions: The high ADFT of internal cardioversion was found to be a risk factor for post-catheter ablation recurrence in patients with long-standing persistent AF but not in those with persistent AF., Competing Interests: Conflicts of Interest There are no conflicts of interest to disclose., (Copyright © 2022. Published by Elsevier B.V.)

Limited data exist on the prevalence and prognosis of isolated posterior ST-segment elevation acute myocardial infarction (STEMI), revealed with a posterior chest lead. Furthermore, the utility of a synthesized-V 7-9 lead in the diagnosis of STEMI is unclear; therefore, we aimed to evaluate its usefulness. We enrolled 142 consecutive patients with STEMI with the culprit lesion on the left circumflex artery (STEMI-LCx) undergoing percutaneous coronary intervention (PCI) between January 2009 and December 2019. We retrospectively checked the ST-segment change of both standard 12-lead and synthesized-V 7-9 lead in all patients with STEMI-LCx. Based on electrocardiogram (ECG) findings, isolated posterior STEMI that was only revealed in synthesized-V 7-9 lead was classified as "STEMI-LCx-synV 7-9 " and the remaining as "STEMI-LCx-12ECG." The prevalence of STEMI-LCx-synV 7-9 in patients with STEMI-LCx was assessed. The incidence of all-cause death, cardiac death, and mechanical complications within 30 days, 3 months, and 1 year was also assessed according to each STEMI-LCx. STEMI-LCx-synV 7-9 and STEMI-LCx-12ECG occurred in 10 (7.0%) and 132 (93.0%) patients, respectively. No significant difference was found in patients' characteristics between the two groups. The patients with STEMI-LCx-synV 7-9 had significantly higher incidences of cardiac death within 3 months and 1 year (30.0% vs. 6.1%, P = 0.031, 30.0% vs. 7.6%, P = 0.050, respectively) and mechanical complications in each follow-up period (20.0% vs. 1.5%, P = 0.025) than those with STEMI-LCx-12ECG. STEMI-LCx-synV 7-9 was observed in 7.0% of the patients with STEMI-LCx. Our findings suggest that the synthesized-V 7-9 lead helps diagnose isolated posterior STEMI and might improve prognosis in patients with STEMI-LCx., (© 2021. Japanese Association of Cardiovascular Intervention and Therapeutics.)

Background: Although short-term mortality in ST-elevation myocardial infarction (STEMI) has improved, data is limited regarding very long-term mortality and concomitant clinical events in STEMI survivors who undergo primary percutaneous coronary intervention (p-PCI). This study aimed to evaluate these parameters at 15 years and to determine the predictors of 15-year mortality in these patients., Methods: The study endpoints were all-cause mortality and cardiac mortality at 15 years. Independent predictors of all-cause mortality were also analyzed. Furthermore, each thrombotic and bleeding event was evaluated., Results: Between January 2004 and December 2006, 260 STEMI survivors who underwent p-PCI (median follow-up period: 3970 days) were evaluated from the Ogaki Municipal hospital registry. The rates of all-cause mortality (cardiac mortality) at 5, 10, and 15 years were 12.1% (4.9%), 23.4% (9.5%), and 34.9% (12.4%), respectively. The cumulative incidences of recurrent myocardial infarction, target vessel revascularization, ischemic stroke, hemorrhagic bleeding, and gastric bleeding at 15 years were 11.3%, 43.6%, 14.3%, 6.9%, and 10.9%, respectively. Cox regression analysis showed that age ≥ 75 years [adjusted hazard ratio (aHR), 7.074, p < 0.001], chronic kidney disease (aHR, 2.320, p = 0.001), left ventricular ejection fraction <40% (aHR, 2.930, p = 0.001), Killip class ≥II at admission (aHR, 2.639, p = 0.003), untreated chronic total occlusion (aHR, 2.090, p = 0.042), and final TIMI grade ≤ 2 (aHR, 1.736, p = 0.048) were independent predictors of all-cause mortality., Conclusion: This study demonstrated that all-cause and cardiac mortality at 15 years were 34.9% and 12.4%, respectively, in all-comers STEMI survivors after p-PCI, indicating that STEMI survivors might have a benign prognosis., Competing Interests: Declaration of competing interest H.I received lecture fees from Astellas Pharma Inc., Astrazeneca Inc., Daiichi-Sankyo Pharma Inc., and MSD K. K. T.A. received lecture fees from Astellas Pharma, AstraZeneca, Bayer, Daiichi Sankyo, and Bristol-Myers Squibb. T.M received lecture fees from Bayel Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Kowa Co., Ltd., MSD K. K., Mitsubishi Tanabe Pharma Co., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K. K., Pfizer Japan Inc., Sanofi-aventis K. K., and Takeda Pharmaceutical Co., Ltd. T.M received unrestricted research grant for Department of Cardiology, Nagoya University Graduate School of Medicine from Astellas Pharma Inc., Daiichi-Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Kowa Co., Ltd., MSD K. K., Mitsubishi Tanabe Pharma Co., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K. K., Otsuka Pharma Ltd., Pfizer Japan Inc., Sanofi-aventis K. K., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Low body mass index (BMI) is a predictor of adverse events in patients with ST-elevated myocardial infarction (STEMI) in Western countries. Because the average BMI of Asians is significantly lower than that of the Western population, the appropriate cut-off BMI value and its role in long-term mortality are unclear in Asian patients. Between January 2006 and December 2017, 1215 patients who underwent percutaneous coronary intervention (PCI) for acute STEMI and were alive at discharge (mean age, 67.7 years; male, 75.4%) were evaluated. The cut-off BMI value, which could predict all-cause mortality within 10 years, was detected using a survival classification and regression tree (CART) model. The causes of death according to the BMI value were evaluated in each group. Based on the CART model, the patients were divided into three groups (BMI < 18 kg/m 2 : 54 patients, 18 kg/m 2  ≤ BMI ≤ 20 kg/m 2 : 109 patients, and BMI > 20 kg/m 2 : 1052 patients). The BMI decreased with age; with an increased BMI, patients with dyslipidemia, diabetes mellitus, and smoking habit increased. During the study period (median, 4.9 years), 194 patients (26.8%) died (cardiac death, 59 patients; non-cardiac death, 135 patients). All-cause mortality was more frequent as the BMI decreased (BMI < 18 kg/m 2 ; 72.8%, 18 kg/m 2  ≤ BMI ≤ 20 kg/m 2 ; 40.5%, and BMI > 20 kg/m 2 ; 22.8%; log-rank p < 0.001). Non-cardiac deaths were more frequent than cardiac deaths in all groups, and the dominance of non-cardiac death was highest in the lowest BMI group. Cut-off BMI values of 18 kg/m 2 and 20 kg/m 2 can predict long-term mortality after PCI in Asian STEMI survivors, whose cut-off value is lower than that in the Western populations. The main causes of death in this cohort differed according to the BMI values., (© 2021. Springer Japan KK, part of Springer Nature.)

Carriers of heterozygous germline BAP1 mutations ( BAP1 +/- ) are affected by the "BAP1 cancer syndrome." Although they can develop almost any cancer type, they are unusually susceptible to asbestos carcinogenesis and mesothelioma. Here we investigate why among all carcinogens, BAP1 mutations cooperate with asbestos. Asbestos carcinogenesis and mesothelioma have been linked to a chronic inflammatory process promoted by the extracellular release of the high-mobility group box 1 protein (HMGB1). We report that BAP1 +/- cells secrete increased amounts of HMGB1, and that BAP1 +/- carriers have detectable serum levels of acetylated HMGB1 that further increase when they develop mesothelioma. We linked these findings to our discovery that BAP1 forms a trimeric protein complex with HMGB1 and with histone deacetylase 1 (HDAC1) that modulates HMGB1 acetylation and its release. Reduced BAP1 levels caused increased ubiquitylation and degradation of HDAC1, leading to increased acetylation of HMGB1 and its active secretion that in turn promoted mesothelial cell transformation., Competing Interests: Competing interest statement: M.C. has a patent issued for BAP1. M.C. and H.Y. have two patents issued for HMGB1. M.C. is a board-certified pathologist who provides consultation for pleural pathology, including medical–legal.