Publications by authors named "Shigeru Oshima"

217 Publications

A potent endocytosis inhibitor Ikarugamycin up-regulates TNF production.

Biochem Biophys Rep 2021 Sep 8;27:101065. Epub 2021 Jul 8.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.

Ikarugamycin (IK) is an antibiotic which has been reported to have a variety of functions, such as inhibition of clathrin-mediated endocytosis (CME), anti-tumor effects and regulation of the immune system. Whether IK influences cytokine production is poorly understood. We have investigated the relationship between IK and production of tumor necrosis factor-α (TNF). TNF plays a pivotal role in pathogenesis of many diseases. Although the dynamics of soluble TNF (sTNF) has been widely explored so far, the functions of the membrane form of TNF (mTNF) have not been fully elucidated. We demonstrated that IK increases the amount of mTNF and prolongs the duration of TNF expression. This effect is unrelated to the shedding activity of disintegrin and metalloproteinase domain-containing protein 17 (ADAM 17). Our results revealed that there is a mechanism to terminate inflammation at the cellular level which IK dysregulates. Furthermore, IK can be a tool to study TNF signaling due to its effect of increasing mTNF expression.
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http://dx.doi.org/10.1016/j.bbrep.2021.101065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274290PMC
September 2021

Oral administration of D-serine prevents the onset and progression of colitis in mice.

J Gastroenterol 2021 Aug 20;56(8):732-745. Epub 2021 Jun 20.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, 113-8519, Japan.

Background: L-amino acids are the predominant forms of organic molecules on the planet, but recent studies have revealed that various foods contain D-amino acids, the enantiomers of L-amino acids. Though diet plays important roles in both the development and progression of inflammatory bowel disease (IBD), to our best knowledge, there has been no report on any potential interactions between D-amino acids and IBD. In this report, we aim to assess the effects of D-serine in a murine model of IBD.

Materials And Methods: To induce chronic colitis, naïve CD4 T cells (CD4 CD62 CD44) from wild-type mice were adoptively transferred into Rag2 mice, after or before the mice were orally administered with D-serine. In vitro proliferation assays were performed to assess naïve CD4 T cell activation under the Th-skewing conditions in the presence of D-serine.

Results: Mice treated with D-serine prior to the induction of colitis exhibited a reduction in T-cell infiltration into the lamina propria and colonic inflammation that were not seen in mice fed with water alone or L-serine. Moreover, D-serine suppressed the progression of chronic colitis when administered after the disease induction. Under in vitro conditions, D-serine suppressed the proliferation of activated CD4 T cells and limited their ability to differentiate to Th1 and Th17 cells.

Conclusion: Our results suggest that D-serine not only can prevent, but also has efficacious effects as a treatment for IBD.
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http://dx.doi.org/10.1007/s00535-021-01792-1DOI Listing
August 2021

Impact of Chronic Kidney Disease on In-Hospital and 3-Year Clinical Outcomes in Patients With Acute Myocardial Infarction Treated by Contemporary Percutaneous Coronary Intervention and Optimal Medical Therapy - Insights From the J-MINUET Study.

Circ J 2021 Sep 3;85(10):1710-1718. Epub 2021 Jun 3.

Department of Cardiology, Gunma Prefectural Cardiovascular Center.

Background: The impact of chronic kidney disease (CKD) on long-term outcomes following acute myocardial infarction (AMI) in the era of modern primary PCI with optimal medical therapy is still in debate.Methods and Results:A total of 3,281 patients with AMI were enrolled in the J-MINUET registry, with primary PCI of 93.1% in STEMI. CKD stage on admission was classified into: no CKD (eGFR ≥60 mL/min/1.73 m); moderate CKD (60>eGFR≥30 mL/min/1.73 m); and severe CKD (eGFR <30 mL/min/1.73 m). While the primary endpoint was all-cause mortality, the secondary endpoint was major adverse cardiac events (MACE), defined as a composite of all-cause death, cardiac failure, myocardial infarction (MI) and stroke. Of the 3,281 patients, 1,878 had no CKD, 1,073 had moderate CKD and 330 had severe CKD. Pre-person-days age- and sex-adjusted in-hospital mortality significantly increased from 0.014% in no CKD through 0.042% in moderate CKD to 0.084% in severe CKD (P<0.0001). Three-year mortality and MACE significantly deteriorated from 5.09% and 15.8% in no CKD through 16.3% and 38.2% in moderate CKD to 36.7% and 57.9% in severe CKD, respectively (P<0.0001). C-index significantly increased from the basic model of 0.815 (0.788-0.841) to 0.831 (0.806-0.857), as well as 0.731 (0.708-0.755) to 0.740 (0.717-0.764) when adding CKD stage to the basic model in predicting 3-year mortality (P=0.013; net reclassification improvement [NRI] 0.486, P<0.0001) and MACE (P=0.046; NRI 0.331, P<0.0001) respectively.

Conclusions: CKD remains a useful predictor of in-hospital and 3-year mortality as well as MACE after AMI in the modern PCI and optimal medical therapy era.
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http://dx.doi.org/10.1253/circj.CJ-20-1115DOI Listing
September 2021

Long-Term Clinical Impact of Cardiogenic Shock and Heart Failure on Admission for Acute Myocardial Infarction.

Int Heart J 2021 May 15;62(3):520-527. Epub 2021 May 15.

Department of Cardiology, Fukuoka University School of Medicine.

Long-term clinical outcomes among patients with cardiogenic shock (CS) and heart failure (HF) who survive the early phase of acute myocardial infarction (AMI) remain uncertain. We investigated 3283 consecutive patients with AMI, selected from a prospective, nation-wide multicenter registry (J-MINUET) database comprising 28 institutions in Japan between July 2012 and March 2014. The 3263 eligible patients were divided into the following three groups: CS-/HF- group (n = 2467, 75.6%); CS-/HF+ group (n = 479, 14.7%); and CS+ group (n = 317, 9.7%). The thirty-day mortality rate in CS+ patients was 32.8%, significantly higher than in CS- patients. Among CS+ patients, multivariate logistic regression analysis identified statin use before admission (Odds ratio (OR) 0.32, 95% confidence interval (CI) 0.14-0.66, P = 0.002), renal deficiency (OR 8.72, 95%CI 2.81-38.67, P < 0.0001) and final thrombolysis in myocardial infarction flow grade (OR 0.42, 95%CI 0.18-0.99, P = 0.046) were associated with 30-day mortality. Landmark Kaplan-Meier analysis showed that mortality rates after 30 days were comparable between CS+ and CS-/HF+ groups but were lower in the CS-/HF- group. Multivariate Cox hazard analysis also showed that hazard risk of mortality after 30 days was comparable between the CS+ and CS-/HF+ groups (Hazard ratio (HR) 1.03, 95%CI 0.63-1.68, P = 0.90), and significantly lower in the CS-/HF- group (HR 0.44, 95%CI 0.32-059, P < 0.0001). In conclusion, AMI patients with CS who survived 30 days experienced worse long-term outcomes compared with those without CS up to 3 years. Attention is required for patients who show HF on admission without CS to improve long-term AMI outcomes.
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http://dx.doi.org/10.1536/ihj.20-646DOI Listing
May 2021

Corrigendum to "CEACAM1 specifically suppresses B cell receptor signaling-mediated activation".

Biochem Biophys Res Commun 2021 Aug 13;565:97. Epub 2021 May 13.

Department of Advanced Therapeutics for GI Diseases, Graduate School of Medical Science, TMDU, Tokyo, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.bbrc.2021.05.006DOI Listing
August 2021

Validation of the atherothrombotic risk score for secondary prevention in patients with acute myocardial infarction: the J-MINUET study.

Heart Vessels 2021 Oct 21;36(10):1506-1513. Epub 2021 Apr 21.

Department of Cardiology, Gunma Prefectural Cardiovascular Center, Maebashi, Japan.

Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention (TRS2°P) is a contemporary risk scoring system for secondary prevention based on nine clinical factors. However, this scoring system has not been validated in other populations. The aim of this study was to validate the TRS2°P in patients with acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention (PCI) in a nationwide registry cohort. Among 3283 consecutive patients with AMI enrolled in the Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET), a total of 2611 patients who underwent primary PCI were included in this study. The performance of the TRS2°P to predict major adverse cardiovascular events (MACE) composed of all-cause death, non-fatal MI, and non-fatal stroke up to 3 years in the present cohort was evaluated. The TRS2°P had modest discriminative performance in this J-MINUET cohort with a c-statistic of 0.63, similar to that in the derived cohort (TRA2°P-TIMI50, c-statistic 0.67). A strong graded relationship between the TRS2°P and 3-year cardiovascular event rates was also observed in the J-MINUET cohort. Age ≥ 75 years, Killip ≥ 2, prior stroke, peripheral artery disease, anemia, and non-ST-elevation myocardial infarction were identified as independent factors for the incidence of MACE. The TRS2°P modestly predicted secondary cardiovascular events among patients with AMI treated by primary PCI in a nationwide cohort of Japan. Further studies are needed to develop a novel risk score better predicting secondary cardiovascular events.
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http://dx.doi.org/10.1007/s00380-021-01840-zDOI Listing
October 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Intraepithelial Lymphocytes Suppress Intestinal Tumor Growth by Cell-to-Cell Contact via CD103/E-Cadherin Signal.

Cell Mol Gastroenterol Hepatol 2021 28;11(5):1483-1503. Epub 2021 Jan 28.

Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.

Background & Aims: The reason why small intestinal cancer is rarer than colorectal cancer is not clear. We hypothesized that intraepithelial lymphocytes (IELs), which are enriched in the small intestine, are the closest immune cells to epithelial cells, exclude tumor cells via cell-to-cell contact.

Methods: We developed DPE-green fluorescent protein (DPE-GFP) × adenomatous polyposis coli; multiple intestinal neoplasia (APC ) mice, which is a T-cell-reporter mouse with spontaneous intestinal tumors. We visualized the dynamics of IELs in the intestinal tumor microenvironment and the interaction between IELs and epithelial cells, and the roles of cell-to-cell contact in anti-intestinal tumor immunity using a novel in vivo live-imaging system and a novel in vitro co-culture system.

Results: In the small intestinal tumor microenvironment, T-cell movement was restricted around blood vessels and the frequency of interaction between IELs and epithelial cells was reduced. Genetic deletion of CD103 decreased the frequency of interaction between IELs and epithelial cells, and increased the number of small intestinal tumors. In the co-culture system, wild-type IELs expanded and infiltrated to intestinal tumor organoids from APC mice and reduced the viability of them, which was cell-to-cell contact and CD103 dependent.

Conclusions: The abundance of IELs in the small intestine may contribute to a low number of tumors, although this system may not work in the colon because of the sparseness of IELs. Strategies to increase the number of IELs in the colon or enhance cell-to-cell contact between IELs and epithelial cells may be effective for the prevention of intestinal tumors in patients with a high cancer risk.
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http://dx.doi.org/10.1016/j.jcmgh.2021.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025200PMC
January 2021

Notch and TNF-α signaling promote cytoplasmic accumulation of OLFM4 in intestinal epithelium cells and exhibit a cell protective role in the inflamed mucosa of IBD patients.

Biochem Biophys Rep 2021 Mar 11;25:100906. Epub 2021 Jan 11.

Department of Gastroenterology and Hepatology, Japan.

Notch signaling is activated in the intestinal epithelial cells (IECs) of patients with inflammatory bowel disease (IBD), and contributes to mucosal regeneration. Our previous study indicated that TNF-α and Notch signaling may synergistically promote the expression of the intestinal stem cell (ISC) marker OLFM4 in human IECs. In the present study, we investigated the gene regulation and function of OLFM4 in human IEC lines. We confirmed that TNF-α and Notch synergistically upregulate the mRNA expression of OLFM4. Luciferase reporter assay showed that OLFM4 transcription is regulated by the synergy of TNF-α and Notch. At the protein level, synergy between TNF-α and Notch promoted cytoplasmic accumulation of OLFM4, which has potential anti-apoptotic properties in human IECs. Analysis of patient-derived tissues and organoids consistently showed cytoplasmic accumulation of OLFM4 in response to NF-κB and Notch activation. Cytoplasmic accumulation of OLFM4 in human IECs is tightly regulated by Notch and TNF-α in synergy. Such cytoplasmic accumulation of OLFM4 may have a cell-protective role in the inflamed mucosa of patients with IBD.
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http://dx.doi.org/10.1016/j.bbrep.2020.100906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808948PMC
March 2021

Functional analysis of isoflavones using patient-derived human colonic organoids.

Biochem Biophys Res Commun 2021 Jan 20;542:40-47. Epub 2021 Jan 20.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan; Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. Electronic address:

Inflammatory bowel disease (IBD) comprises two major subtypes, ulcerative colitis (UC) and Crohn's disease, which are multifactorial diseases that may develop due to genetic susceptibility, dysbiosis, or environmental factors. Environmental triggers of IBD include food-borne factors, and a previous nationwide survey in Japan identified pre-illness consumption of isoflavones as a risk factor for UC. However, the precise mechanisms involved in the detrimental effects of isoflavones on the intestinal mucosa remain unclear. The present study employed human colonic organoids (hCOs) to investigate the functional effect of two representative isoflavones, genistein and daidzein, on human colonic epithelial cells. The addition of genistein to organoid reformation assays significantly decreased the number and size of reformed hCOs compared with control and daidzein treatment, indicating an inhibitory effect of genistein on colonic cell/progenitor cell function. Evaluation of the phosphorylation status of 49 different receptor tyrosine kinases showed that genistein selectively inhibited phosphorylation of epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (HGFR). We established a two-dimensional wound-repair model using hCOs and showed that genistein significantly delayed the overall wound-repair response. Our results collectively show that genistein may exert its detrimental effects on the intestinal mucosa via negative regulation of stem/progenitor cell function, possibly leading to sustained mucosal injury and the development of UC.
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http://dx.doi.org/10.1016/j.bbrc.2021.01.021DOI Listing
January 2021

Nickel ions attenuate autophagy flux and induce transglutaminase 2 (TG2) mediated post-translational modification of SQSTM1/p62.

Biochem Biophys Res Commun 2021 Jan 19;542:17-23. Epub 2021 Jan 19.

Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address:

Nickel, the most frequent contact allergy cause, is widely used for various metallic materials and medical devices. Autophagy is an intracellular protein degradation system and contributes to metal recycling. However, it is unclear the functions of nickel in autophagy. We here demonstrated that NiCl2 induced microtubule-associated protein 1 light chain 3 (LC3)-II and LC3 puncta, markers of autophagosomes. Bafilomycin A1 (BafA1) treatment did not enhance LC3 puncta under NiCl2 stimulation, suggesting that NiCl2 did not induce autophagic flux. In addition, NiCl2 promotes the accumulation of SQSTM1/p62 and increased SQSTM1/p62 colocalization with lysosomal-associated membrane protein 1 (LAMP1). These data indicated that NiCl2 attenuates autophagic flux. Interestingly, NiCl2 induced the expression of the high-molecular-weight (MW) form of SQSTM1/p62. Inhibition of NiCl2-induced reactive oxygen species (ROS) reduced the high-MW SQSTM1/p62. We also showed that NiCl2-induced ROS activate transglutaminase (TG) activity. We found that transglutaminase 2 (TG2) inhibition reduced high-MW SQSTM1/p62 and SQSTM1/p62 puncta under NiCl2 stimulation, indicating that TG2 regulates SQSTM1/p62 protein homeostasis under NiCl2 stimulation. Our study demonstrated that nickel ion regulates autophagy flux and TG2 restricted nickel-dependent proteostasis.
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http://dx.doi.org/10.1016/j.bbrc.2021.01.023DOI Listing
January 2021

CEACAM1 specifically suppresses B cell receptor signaling-mediated activation.

Biochem Biophys Res Commun 2021 01 21;535:99-105. Epub 2020 Dec 21.

Department of Advanced Therapeutics for GI Diseases, Graduate School of Medical Science, TMDU, Tokyo, Japan. Electronic address:

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expressed in T cells may regulate immune responses in the gut. In addition to T cells, B cells are also an important population in the gut-associated lymphoid tissues that orchestrate mucosal homeostasis. However, the role of CEACAM1 in B cells has not been elucidated. We herein analyzed mature B cells to determine the functions of CEACAM1. Flow cytometry revealed high expression of CEACAM1 on B cells in secondary lymphoid tissues. Cytokine production induced by activation of B cell receptor (BCR) signaling was suppressed by CEACAM1 signaling in contrast to that associated with either Toll-like receptor 4 or CD40 signaling. Confocal microscopy revealed co-localization of CEACAM1 and BCR when activated with anti-Igμ F(ab') fragment. Overexpression of CEACAM1 in a murine B cell line, A20, resulted in reduced expressions of activation surface markers with decreased Ca influx after BCR signal activation. Overexpression of CEACAM1 suppressed BCR signal cascade in A20 cells in association with decreased spontaneous proliferation. Our results suggest that CEACAM1 can regulate BCR-mediated mature B cell activation in lymphoid tissues. Therefore, further studies of this molecule may lead to greater insights into the mechanisms of immune responses within peripheral tissues and the potential treatment of inflammatory diseases.
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http://dx.doi.org/10.1016/j.bbrc.2020.11.126DOI Listing
January 2021

Impact of Age on Gender Difference in Long-term Outcome of Patients With Acute Myocardial Infarction (from J-MINUET).

Am J Cardiol 2021 03 3;142:5-13. Epub 2020 Dec 3.

Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.

Although gender difference in long-term outcomes after acute myocardial infarction have been shown previously, impact of age on gender difference is still controversial. This study focused on the association between age and gender difference in long-term outcome. We analyzed data from 3,283 consecutive patients who were included in a prospective, nationwide, multicenter registry (Japan Registry of Acute Myocardial Infarction Diagnosed by Universal Definition) from 2012 to 2014. The primary end point was the major adverse cardiovascular event (MACE), which was defined as a composite of death, myocardial infarction, stroke, heart failure, and revascularization for unstable angina during 3 years. Patients were divided into 4 strata according to age: those with age <65 years (group 1: n = 1161), 65 to 74 years (group 2: n = 954), 75 to 84 years (group 3: n = 866) and 84< years (group 4: n = 302). Although the crude incidence of 3-year MACE was significantly higher in women than men (36.4% vs. 28.5%, p <0.001), there was not significant gender difference in each group (group 1, 19.6% vs 19.0%, p = 0.74; group 2, 33.1% vs 28.3%, p = 0.25; group 3, 38.9% vs 39.6%, p = 0.54; and group 4, 54.0% vs 56.8%, p = 0.24). In conclusion, although women had higher crude incidence of 3-year MACE than men, there was no gender difference in each group.
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http://dx.doi.org/10.1016/j.amjcard.2020.11.042DOI Listing
March 2021

Clinical characteristics and in-hospital outcomes in patients aged 80 years or over with cardiac troponin-positive acute myocardial infarction -J-MINUET study.

J Cardiol 2021 02 13;77(2):139-146. Epub 2020 Sep 13.

Department of Cardiology, Gunma Prefectural Cardiovascular Center, Maebashi, Japan.

Background: The prevalence of acute myocardial infarction (AMI) in elderly people is increasing worldwide. However, their characteristics and prognosis have been rarely investigated. This study aimed to investigate the characteristics and prognosis in elderly patients with cardiac troponin-positive AMI.

Methods: Consecutive patients with AMI from the J-MINUET study were divided into the following 3 groups: patients aged less than 65 years, those aged between 65 and 79 years, and those aged 80 years or over. Their characteristics and in-hospital outcomes were compared.

Results: Patients with AMI aged 80 years or over had the highest incidence of female gender, and the highest incidence of hypertension, chronic kidney disease, and cardiovascular disease, such as peripheral artery disease, atrial fibrillation, and stroke, whereas they had the lowest body mass index, and the lowest incidence of current smoker, diabetes mellitus, and dyslipidemia. Patients with AMI aged 80 years or over had significantly longer onset to door time and longer door to device time, and lower peak creatine kinase (CK). The incidence of ST-segment elevation myocardial infarction (STEMI) was the lowest in the AMI patients aged 80 years or over, but the patients had a higher incidence of in-hospital death and cardiac failure than the other two groups. In addition, the presentation with STEMI and non-ST-segment elevation myocardial infarction with CK elevation among patients aged 80 years or over showed the highest incidence of in-hospital death and cardiac failure.

Conclusions: J-MINUET showed different clinical characteristics between the aged and younger populations. The incidence of in-hospital death and cardiac failure in patients aged 80 years or over with AMI was poorer than their younger counterparts.
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http://dx.doi.org/10.1016/j.jjcc.2020.08.006DOI Listing
February 2021

Prognostic Impact of B-Type Natriuretic Peptide on Long-Term Clinical Outcomes in Patients with Non-ST-Segment Elevation Acute Myocardial Infarction Without Creatine Kinase Elevation.

Int Heart J 2020 Sep 12;61(5):888-895. Epub 2020 Sep 12.

Department of Cardiology, Fukuoka University School of Medicine.

Although B-type natriuretic peptide (BNP) has gradually gained recognition as an indicator in risk stratification for patients with acute myocardial infarction (AMI), the prognostic impact on long-term clinical outcomes in patients with non-ST-segment elevation acute myocardial infarction (NSTEMI) without creatine kinase (CK) elevation remains unclear.This prospective multicenter study assessed 3,283 consecutive patients with AMI admitted to 28 institutions in Japan between 2012 and 2014. We analyzed 218 patients with NSTEMI without CK elevation (NSTEMI-CK) for whom BNP was available. In the NSTEMI-CK group, patients were assigned to high- and low-BNP groups according to BNP values (cut-off BNP, 100 pg/mL). The primary endpoint was defined as a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, cardiac failure, and urgent revascularization for unstable angina up to 3 years. Primary endpoints were observed in 60 (33.3%) events among patients with NSTEMI-CK. Kaplan-Meier analysis revealed a significantly higher event rate for primary endpoints among patients with high BNP (log-rank P < 0.001). After adjusting for covariates, a higher BNP level was significantly associated with long-term clinical outcomes in NSTEMI-CK (adjusted hazard ratio, 4.86; 95% confidence interval, 2.18-12.44; P < 0.001).The BNP concentration is associated with adverse long-term clinical outcomes among patients with NSTEMI-CK who are considered low risk. Careful clinical management may be warranted for secondary prevention in patients with NSTEMI-CK with high BNP levels.
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http://dx.doi.org/10.1536/ihj.20-190DOI Listing
September 2020

Impact of peripheral artery disease on prognosis after myocardial infarction: The J-MINUET study.

J Cardiol 2020 10 9;76(4):402-406. Epub 2020 Jun 9.

Fukuoka University School of Medicine, Fukuoka, Japan.

Background: Patients with peripheral artery disease (PAD) are at high risk of cardiovascular events, including myocardial infarction (MI), stroke, and cardiovascular death. However, the impact of PAD on prognosis in Japanese patients with acute MI remains unclear.

Methods: The Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET) is a prospective multicenter registry that registered 3283 patients with acute MI. Among them, 2970 patients with available data of PAD were divided into the following 4 groups: 2513 patients without prior MI or PAD (None group), 320 patients with only prior MI (Prior MI group), 100 patients with only PAD (PAD group), and 37 patients with both previous MI and PAD (Both group). The primary endpoint was a composite of all-cause death, non-fatal MI, non-fatal stroke, cardiac failure, and urgent revascularization for unstable angina.

Results: The 3-year cumulative incidence of the primary endpoint was 26.9% in None group, 41.4% in Prior MI group, 48.0% in PAD group, and 60.3% in Both group (p < 0.001). In multivariate analysis, hazard ratio using None group as reference was 1.55 (95% confidence intervals 1.25-1.91; p < 0.001) for MI group, 2.26 (1.61-3.07; p < 0.001) for PAD group, and 2.52 (1.52-3.90; p < 0.001) for Both group.

Conclusions: Concomitant PAD was associated with poor prognosis in Japanese patients with acute MI.
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http://dx.doi.org/10.1016/j.jjcc.2020.05.014DOI Listing
October 2020

Admission During Off-Hours Does Not Affect Long-Term Clinical Outcomes of Japanese Patients with Acute Myocardial Infarction.

Int Heart J 2020 Mar 14;61(2):215-222. Epub 2020 Mar 14.

Department of Cardiology, Fukuoka University School of Medicine.

Discordant results have been reported on outcomes of acute myocardial infarction (AMI) patients who present during off-hours.We investigated 3283 consecutive patients with AMI who were selected from the prospective, nationwide, multicenter registry (J-MINUET) database comprising 28 institutions in Japan between July 2012 and March 2014 to determine the current impact of off-hours presentation (defined as weekends, holidays, and weekdays from 8:01 PM to 7:59 AM) at hospitals on long-term clinical outcomes. The primary endpoint was a composite of all-cause death, non-fatal MI, non-fatal stroke, cardiac failure, and urgent revascularization for unstable angina for up to 3 years from the index event.During off-hours, 52% of patients presented. Primary percutaneous coronary intervention was performed in 85% of patients, and the door-to-balloon time was comparable between off-hours and regular hours (74, interquartile range [IQR] 52 to 113 versus 75, IQR 52 to 126 minutes, P = 0.34). Rate of overall primary endpoint overall did not overall significantly differ (25.3% versus 23.5%, log-rank P = 0.26), in patients with ST-elevation myocardial infarction (STEMI) (log-rank P = 0.93) and in patients with non-ST-elevation myocardial infarction (NSTEMI) (log-rank P = 0.14). Multivariate Cox regression analysis showed that off-hours presentation was not significantly associated with long-term clinical events in all cohorts.The impact of presentation during off-hours or regular hours on the long-term clinical outcomes of Japanese patients with AMI is comparable in contemporary practice.
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http://dx.doi.org/10.1536/ihj.19-434DOI Listing
March 2020

TGF-β promotes fetal gene expression and cell migration velocity in a wound repair model of untransformed intestinal epithelial cells.

Biochem Biophys Res Commun 2020 04 1;524(3):533-541. Epub 2020 Feb 1.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8519, Japan; Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8519, Japan. Electronic address:

The early-phase wound repair response of the intestinal epithelium is characterized by rapid and organized cell migration. This response is regulated by several humoral factors, including TGF-β. However, due to a lack of appropriate models, the precise response of untransformed intestinal epithelial cells (IECs) to those factors is unclear. In this study, we established an in vitro wound repair model of untransformed IECs, based on native type-I collagen. In our system, IECs formed a uniform monolayer in a two-chamber culture insert and displayed a stable wound repair response. Gene expression analysis revealed significant induction of Apoa1, Apoa4, and Wnt4 during the collagen-guided wound repair response. The wound repair response was enhanced significantly by the addition of TGF-β. Surprisingly, addition of TGF-β induced a set of genes, including Slc28a2, Tubb2a, and Cpe, that were expressed preferentially in fetal IECs. Moreover, TGF-β significantly increased the peak velocity of migrating IECs and, conversely, reduced the time required to reach the peak velocity, as confirmed by the motion vector prediction (MVP) method. Our current in vitro system could be employed to assess other humoral factors involved in IEC migration and could contribute to a deeper understanding of the wound repair potentials of untransformed IECs.
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http://dx.doi.org/10.1016/j.bbrc.2020.01.108DOI Listing
April 2020

Receptor-Interacting Protein Kinase 3 (RIPK3) inhibits autophagic flux during necroptosis in intestinal epithelial cells.

FEBS Lett 2020 05 16;594(10):1586-1595. Epub 2020 Feb 16.

Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Japan.

Autophagy is an intracellular process that regulates the degradation of cytosolic proteins and organelles. Dying cells often accumulate autophagosomes. However, the mechanisms by which necroptotic stimulation induces autophagosomes are not defined. Here, we demonstrate that the activation of necroptosis with TNF-α plus the cell-permeable pan-caspase inhibitor Z-VAD induces LC3-II and LC3 puncta, markers of autophagosomes, via the receptor-interacting protein kinase 3 (RIPK3) in intestinal epithelial cells. Surprisingly, necroptotic stimulation reduces autophagic activity, as evidenced by enlarged puncta of the autophagic substrate SQSTM1/p62 and its increased colocalization with LC3. However, necroptotic stimulation does not induce the lysosomal-associated membrane protein 1 (LAMP1) nor syntaxin 17, which mediates autophagosome-lysosome fusion, to colocalize with LC3. These data indicate that necroptosis attenuates autophagic flux before the lysosome fusion step. Our findings may provide insights into human diseases involving necroptosis.
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http://dx.doi.org/10.1002/1873-3468.13748DOI Listing
May 2020

Guideline adherence and long-term clinical outcomes in patients with acute myocardial infarction: a Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition (J-MINUET) substudy.

Eur Heart J Acute Cardiovasc Care 2020 Dec 24;9(8):939-947. Epub 2020 Jan 24.

Department of Cardiology, Fukuoka University School of Medicine, Japan.

Background: The association between guideline adherence and long-term outcomes in patients with acute myocardial infarction in real-world clinical practice remains unclear.

Methods: We investigated 3283 consecutive patients with acute myocardial infarction who were selected from a prospective, nation-wide, multicentre registry (J-MINUET) database covering 28 institutions in Japan between July 2012 and March 2014. Among the 2757 eligible patients, we evaluated the use of seven guideline-recommended therapies, including urgent revascularisation, door-to-balloon time of 90 minutes or less, and five discharge medications (P2Y12 inhibitors on aspirin, beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statins, lipid-lowering drugs). The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, cardiac failure and urgent revascularisation for unstable angina up to 3 years.

Results: The overall median composite guideline adherence was 85.7%. Patients were divided into the following three groups: complete (100%) adherence group (=862); moderate adherence (75% to <100%) group (=911); and low adherence (0-75%) group (=984). The rate of adverse cardiovascular events was significantly lower in the complete adherence group than in the low and moderate adherence groups (log rank <0.0001). Multivariate Cox regression analysis showed complete guideline adherence was also significantly associated with lower adverse cardiovascular events compared with low guideline adherence (hazard ratio 0.66; 95% confidence interval 0.52-0.85; =0.001).

Conclusion: The use of guideline-based therapies for patients with acute myocardial infarction in contemporary clinical practice was associated with significant decreases in adverse long-term clinical outcomes.

Trial Registration: UMIN Unique trial Number: UMIN000010037.
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http://dx.doi.org/10.1177/2048872620902024DOI Listing
December 2020

CD8αα T cells show amoeboid shape and frequent morphological change in vitro, and localize to small intestinal intraepithelial region in vivo.

Biochem Biophys Res Commun 2020 03 19;523(2):328-335. Epub 2019 Dec 19.

Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University (TMDU), Tokyo, Japan; Advanced Research Institute, TMDU, Tokyo, Japan.

Intraepithelial lymphocytes (IELs) are very unique in the intestinal immune system. They include γδT cells and CD4CD8TCRαβT cells (double negative: DNT), both of which are specific for the intestine, in addition to CD4 and CD8 T cells. IELs exist within the monolayer of the intestinal epithelial cells and dynamically move between lamina propria (LP) and intraepithelial (IE) region. The localization and movement patterns of IEL subsets and the regulatory factors have been unknown. Here, we developed a novel in vitro live imaging system and quantified the motility and morphological changes among subsets of IELs. We identified CD8αα as the key regulatory factor. IELs, especially γδ and DNT cells, showed amoeboid shape and frequent morphological change, while most T cells in MLN or SP showed round shape in vitro. TCR signal, IL-15, gut microbes, CCL25, and integrin αEβ7 expression were non-essential for IEL movement in vitro. CD8αα cells showed higher motility and larger morphological changes than CD8αα cells. Adoptive transferred CD8ααCD4-IELs localized to IE region of recipient NSG mice, while CD8ααCD4-IELs localized to the LP. Our results showed that the CD8αα/TL signal is essential for the localization of IELs to IE region in vivo. CD8αα/TL may be an effective target to increase the number of IELs, which protects against intestinal infection, allergy, tumorigenesis or inflammation.
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http://dx.doi.org/10.1016/j.bbrc.2019.12.021DOI Listing
March 2020

High-fat diet-derived free fatty acids impair the intestinal immune system and increase sensitivity to intestinal epithelial damage.

Biochem Biophys Res Commun 2020 02 3;522(4):971-977. Epub 2019 Dec 3.

Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University (TMDU), Tokyo, Japan; Advanced Research Institute, TMDU, Tokyo, Japan.

In Japan and other Asian countries, increased fat uptake induced by a westernized diet is thought to be associated with an increased incidence of inflammatory bowel disease, colorectal cancer and food allergies; however, the mechanism for this remains unclear. High-fat diet (HFD)-fed mice are common animal models used to examine the effect of fat intake in vivo. HFDs are reported to exacerbate DSS-induced colitis and intestinal tumorigenesis, but the effect of HFDs on the intestines before disease induction is often overlooked. We found that the intestinal and gut-associated lymphoid tissue (GALT) morphology of HFD-fed mice differed from that of standard diet (SD)-fed mice. To clarify the mechanism by which fat intake increases intestinal diseases, we analyzed the morphological and immunological aspects of the intestines of HFD-fed mice as well as the molecular mechanisms and physiology. Feeding an HFD for 3 weeks induced atrophy of the small intestine, colon and GALT and reduced the number of small intestinal intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs). Feeding an HFD for only one day reduced the number of small intestinal (SI)-IELs and SI-LPLs. The effect of feeding a 3-week HFD continued for 2 weeks after returning to the SD. The effect of the HFD on the intestinal immune system was independent of the gut microbes. We hypothesized that the cytotoxicity of the abundant HFD-derived free fatty acids in the intestinal lumen impairs the intestinal immune system. Both saturated and unsaturated free fatty acids were toxic to intestinal T-cells in vitro. Orally administering free fatty acids reduced the number of SI-IELs and LPLs. Using a lipase inhibitor to reduce the luminal free fatty acids attenuated the HFD-induced changes in the intestinal immune system, while using a statin to reduce the serum free fatty acids did not. Thus, HFD-induced free fatty acids damaged the intestines; this effect was termed "intestinal lipotoxicity". Because sustained reduction of SI-LPLs after HFD feeding exacerbated indomethacin-induced small intestinal damage, lipotoxicity to the human intestines incurred by consuming a westernized diet in Japan may increase intestinal diseases such as IBD, colorectal cancer or food allergies.
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http://dx.doi.org/10.1016/j.bbrc.2019.11.158DOI Listing
February 2020

Relationship Between Exercise Oscillatory Ventilation Loop and Prognosis of Heart Failure.

Circ J 2019 07 28;83(8):1718-1725. Epub 2019 Jun 28.

Department of Cardiology, Gunma Prefectural Cardiovascular Center.

Background: The cardiopulmonary exercise test (CPX) is a tool for evaluating disease severity and limitations in activities of daily living in patients with cardiac disorders. However, few studies have evaluated the association between exercise oscillatory ventilation (EOV) severity and prognosis in heart failure (HF) patients with EOV. EOV severity can be evaluated by detecting endtidal COpressure (PETCO, an indicator of the arterial partial pressure of CO(PaCO)) and minute ventilation, which is a reflection of the respiratory response to elevated CO. We hypothesized that the magnitude of EOV severity can predict the severity and prognosis of cardiac disorders and aimed to validate this hypothesis.Methods and Results:In total, 2,043 patients who underwent symptom-limited maximal CPX between 2010 and 2016 were evaluated. We enrolled 70 patients who had HF with reduced ejection fraction (HFrEF) and EOV. The endpoint was cardiovascular death. During a median follow-up of 4.3 years, 34 participants died (48%). Those who died showed significantly larger EOV loop size and lower hemoglobin (Hb) levels than those who survived (17.3±7.0 cmvs. 12.8±6.1 cm, P<0.001; 12.2±1.2 g/dL vs. 13.2±2.9 g/dL, P=0.004). Cox regression analyses revealed Hb levels and EOV loop size as independent predictors of cardiovascular death in HFrEF patients with EOV.

Conclusions: EOV loop size was associated with cardiovascular death of HFrEF patients with EOV.
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http://dx.doi.org/10.1253/circj.CJ-18-1047DOI Listing
July 2019

Atrial giant cell myocarditis after atrial fibrillation ablation.

Eur Heart J Case Rep 2018 Jun 19;2(2):yty065. Epub 2018 May 19.

Department of Cardiology, Gunma Prefectural Cardiovascular Center, 3-12 Kameizumimachi kou, Maebashi, Japan.

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http://dx.doi.org/10.1093/ehjcr/yty065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177020PMC
June 2018

Ubiquitin D is Upregulated by Synergy of Notch Signalling and TNF-α in the Inflamed Intestinal Epithelia of IBD Patients.

J Crohns Colitis 2019 Mar;13(4):495-509

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.

Background And Aims: The intestinal epithelium of inflammatory bowel disease [IBD] patients is exposed to various pro-inflammatory cytokines, most notably tumour necrosis factor alpha [TNF-α]. We have previously shown that the Notch signalling pathway is also upregulated in such an epithelium, contributing to intestinal epithelial cell [IEC] proliferation and regeneration. We aimed to reproduce such environment in vitro and explore the gene regulation involved.

Methods: Human IEC cell lines or patient-derived organoids were used to analyse Notch- and TNF-α-dependent gene expression. Immunohistochemistry was performed to analyse expression of ubiquitin D [UBD] in various patient-derived intestinal tissues.

Results: In human IEC cell lines, we found that Notch signalling and TNF-α-induced NFκB signalling are reciprocally regulated to promote expression of a specific gene subset. Global gene expression analysis identified UBD to be one of the most highly upregulated genes, due to synergy of Notch and TNF-α. The synergistic expression of UBD was regulated at the transcriptional level, whereas the UBD protein had an extremely short half-life due to post-translational, proteasomal degradation. In uninflamed intestinal tissues from IBD patients, UBD expression was limited to IECs residing at the crypt bottom. In contrast, UBD-expressing IECs were seen throughout the crypt in inflamed tissues, indicating substantial induction by the local inflammatory environment. Analysis using patient-derived organoids consistently confirmed conserved Notch- and TNF-α-dependent expression of UBD. Notably, post-infliximab [IFX] downregulation of UBD reflected favourable outcome in IBD patients.

Conclusion: We propose that UBD is a novel inflammatory-phase protein expressed in IECs, with a highly rapid responsiveness to anti-TNF-α treatment.
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http://dx.doi.org/10.1093/ecco-jcc/jjy180DOI Listing
March 2019

Genetic and environmental factors drive personalized medicine for Crohn's disease.

J Clin Invest 2018 11 15;128(11):4758-4760. Epub 2018 Oct 15.

The introduction of anti-TNF antibody therapy has changed the course of treatment for Crohn's disease. However, the fundamental mechanism for the onset of Crohn's disease is still unknown, and the treatment strategy for this disease remains suboptimal. The assessment of the disease phenotype based on key environmental factors and genetic background may indicate options for the personalized treatment of Crohn's disease. In this issue of the JCI, Liu et al. show that consumption of tobacco and the mutation of ATG16L1T300A, a prevalent Crohn's disease susceptibility allele, drive defects in cells at the bottom of the intestinal crypt, the Paneth cells. These factors may provide novel targets for personalized medicine.
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http://dx.doi.org/10.1172/JCI124303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205394PMC
November 2018

Glucagon secretion determined by the RIA method is lower in patients with low left ventricular ejection fraction: The new glass study.

Diabetes Res Clin Pract 2018 Oct 10;144:260-269. Epub 2018 Sep 10.

Gunma Prefectural Cardiovascular Center, Department of Cardiology, 3-12 Kameizumimachi, Maebashi, Gunma 371-0004, Japan. Electronic address:

Aims: We investigated the glucagon levels in patients with heart failure (HF), using long oral glucose tolerance test (OGTT).

Methods: In this prospective observational study, we enrolled 30 undiagnosed diabetes patients (age 69 ± 10 years, 70% males, HbA1c 43 mmol/mol). A 4-h OGTT was performed. Glucose, insulin, and glucagon (radioimmunoassay [RIA] and sandwich ELISA [S-W] methods) were evaluated during 4-h. We compared glucagon levels between HF and non-HF patients.

Results: There were 11 HF and 19 non-HF patients. In patients with HF, glucagon (S-W) during 4-h was lower than in patients without HF, with no significant difference. The area under the curve (AUC) of glucagon (RIA) during 4-h was significantly lower among HF patients. Moreover, in patients with reduced left ventricular ejection fraction (LVEF) (<40%), AUC glucagon (RIA) was significantly lower than in patients with non-reduced EF (≥40%). However, there was no difference in glucagon values between the high E/e' (≥13.0) and low E/e' (<13.0) groups.

Conclusions: Although glucagon (S-W) showed no significant difference in patients with and without HF, especially reduced LVEF, glucagon (RIA) secretion was significantly lower in HF patients than in patients without HF. It is suggested that low glucagon secretion might be correlated with low EF.
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http://dx.doi.org/10.1016/j.diabres.2018.09.001DOI Listing
October 2018

Pre-Procedural Thrombolysis in Myocardial Infarction Flow in Patients with ST-Segment Elevation Myocardial Infarction.

Int Heart J 2018 Sep 29;59(5):920-925. Epub 2018 Aug 29.

Department of Cardiology, Gunma Prefectural Cardiovascular Center.

It has been shown that the patency of an infarct-related artery (IRA) before primary percutaneous coronary intervention determines post-procedural success, better preservation of left ventricular function, and lower in-hospital mortality. However, the factors associated with pre-procedural Thrombolysis In Myocardial Infarction (TIMI) flow have not been fully investigated.The Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET) is a prospective multicenter registry conducted at 28 Japanese medical institutions between July 2012 and March 2014. We enrolled 3,283 consecutive patients with acute myocardial infarction who were admitted to a participating institution within 48 hours of symptom onset. There were 2,262 patients (68.9%) with ST-elevation myocardial infarction (STEMI), among whom 2,182 patients underwent emergent or urgent coronary angiography.Pre-procedural TIMI flow grade 3 was related to post-procedural TIMI flow grade 3 (P < 0.001), lower enzymatic infarct size (P < 0.001), lower ventricular tachycardia and ventricular fibrillation (P = 0.049), and lower in-hospital mortality (P = 0.020). A history of antiplatelet drug use was associated with pre-procedural TIMI flow.Antiplatelet drug use on admission was associated with pre-procedural TIMI flow. The patency of the IRA in patients with STEMI was related to procedural success and decreased enzymatic infarct size, fatal arrhythmic events, and in-hospital mortality.
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http://dx.doi.org/10.1536/ihj.17-518DOI Listing
September 2018

Direct Comparison of Severity Grading Assessed by Two-Dimensional, Three-Dimensional, and Doppler Echocardiography for Predicting Prognosis in Asymptomatic Aortic Stenosis.

J Am Soc Echocardiogr 2018 10 27;31(10):1080-1090.e3. Epub 2018 Jul 27.

Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia. Electronic address:

Background: Reliable assessment of aortic stenosis (AS) severity relies on stroke volume (SV) determination using Doppler echocardiography, but it can also be estimated with two-dimensional/three dimensional echocardiography (2DE/3DE). The aim of this study was to compare SV measurements and AS subgroup classifications among the three modalities and determine their prognostic strength in asymptomatic AS.

Methods: We prospectively enrolled 359 patients with asymptomatic AS. SV was determined using three methods, and the patients were divided into four AS subgroups according to indexed aortic valve area (iAVA) and SV index (SVI) determined by each method and mean pressure gradient. The primary end point was major adverse cardiovascular events (MACEs), which included cardiac death, ventricular fibrillation, heart failure, and aortic valve replacement. We also assessed the presence or absence of upper septal hypertrophy.

Results: Doppler-derived SVI was significantly larger than that derived from 2DE/3DE with modest correlations (r = 0.33 and 0.47). Thus, group classification varied substantially by modality. During the median follow-up period of 17 months, 112 patients developed a major adverse cardiovascular event. Although iAVA assessed by Doppler echocardiography had a significantly better net reclassification improvement compared with iAVA by 2DE or 3DE, prognostic values were nearly identical among the three methods. Ventricular septal geometry affected the accuracy of risk stratification.

Conclusions: AS severity grading varied considerably according to the methods applied for calculating SV. Thus, SV measurements are not interchangeable, even though their prognostic power is similar. Hence, examiners should select one of the three methods to assess AS severity and should use the same method in longitudinal examinations.
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http://dx.doi.org/10.1016/j.echo.2018.05.006DOI Listing
October 2018

Uninterrupted vs. interrupted periprocedural direct oral anticoagulants for catheter ablation of atrial fibrillation: a prospective randomized single-centre study on post-ablation thrombo-embolic and haemorrhagic events.

Europace 2019 Feb;21(2):259-267

Division of Cardiology, Gunma Prefectural Cardiovascular Center, 3-12 Kameizumi-machi, Maebashi City, Gunma, Japan.

Aims: This prospective, randomized, single-centre study aimed to directly compare the safety and efficacy of uninterrupted and interrupted periprocedural anticoagulation protocols with direct oral anticoagulants (DOACs) in patients undergoing catheter ablation of non-valvular atrial fibrillation (NVAF).

Methods And Results: We randomly assigned 846 NVAF patients receiving DOACs prior to ablation to uninterruption (n = 422) or interruption (n = 424) of the DOACs on the day of the procedure. The primary endpoint was a composite of symptomatic thromboembolisms and major bleeding events within 30 days after the ablation. Secondary endpoints included symptomatic and silent thromboembolisms and major and minor bleeding events. The primary endpoint occurred in 0.7% of the uninterrupted DOAC group [1 transient ischaemic attack (TIA) and 2 major bleeding events] and 1.2% of the interrupted DOAC group (1 TIA and 4 major bleeding events) (P = 0.480). The incidence of major and minor bleeding was comparable between the two groups (0.5% vs. 0.9%, P = 0.345; 5.9% vs. 5.4%, P = 0.753). Silent cerebral ischaemic lesions (SCILs) were observed in 138 (20.9%) of the 661 patients undergoing post-ablation magnetic resonance (MR) imaging. The uninterrupted and interrupted DOAC groups revealed a similar incidence of SCILs (19.8% vs. 22.0%, P = 0.484) and percentage of SCILs with disappearance on follow-up MR imaging (77.8% vs. 82.1%, P = 0.428).

Conclusion: Both the uninterrupted and interrupted DOAC protocols revealed a low risk of symptomatic thromboembolisms and major bleeding events and similar incidence of SCILs and minor bleeding events and may be feasible for periprocedural anticoagulation in NVAF patients undergoing catheter ablation.
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http://dx.doi.org/10.1093/europace/euy148DOI Listing
February 2019
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