研究活動情報

• Interleukin-6 Enhances Localized Immune Cell Infiltration and Deep Vein Thrombosis Resolution at the Distal Edge.

  Arinal Chairul Achyar, Tetsuya Hara, Aditya Adinata, Yoko Suzuki, Makoto Nishimori, Ken-Ichi Hirata, Hiromasa Otake, Noriaki Emoto

  Inflammation directed by immune cells is pivotal in the development of deep vein thrombosis (DVT). Disruption in the infiltration of these cells can lead to dysregulation of thrombus organization and increase the risk of deadly embolization. Although the general importance of the cytokine interleukin-6 (IL-6) in immune responses is well documented, its role in acute DVT remains largely unknown. Here, we elaborate on how IL-6 governs acute inflammation and the subsequent organization and early resolution of DVT in vivo. We induced DVT in mice via total inferior vena cava ligation and infused them with either recombinant IL-6 or phosphate-buffered saline (PBS) as a control. Exogenous IL-6 reduced DVT burden by 2 and 4 days with accelerated distal edge organization, characterized by well-demarcated fibrosis-like white lesions containing abundant fibrin-collagen, neutrophils, platelets, Arg1+ monocytes, von Willebrand factor, laminin, myofibroblasts, and neovascular channels at the expense of erythrocytes. IL-6 upregulated intrathrombi chemokines, proinflammatory cytokines, and platelet-leukocyte surface markers in the distal region. This IL-6-heightened localized inflammatory response led to extracellular matrix remodeling, which is essential for DVT organization and early resolution. As observed by two-photon microscopy in stasis- and irradiation-induced saphenous vein thrombosis, IL-6 stimulated leukocytes to rapidly infiltrate the thrombus in parallel with venous flow through the distal edge. IL-6-augmented thrombus organization, visualized by rhodamine 6G-labeled platelet-leukocyte accumulation, prompted early resolution, as determined by the reduced thrombus area. Ultimately, IL-6 enhances DVT organization by amplifying localized leukocyte migration and orchestrating acute inflammation involving platelets, thereby expediting the early resolution of DVT.

  2025年07月, American journal of physiology. Heart and circulatory physiology, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Identifying heart failure dynamics using multi-point electrocardiograms and deep learning.

  Yu Nishihara, Makoto Nishimori, Satoki Shibata, Masakazu Shinohara, Ken-Ichi Hirata, Hidekazu Tanaka

  AIMS: Heart failure (HF) hospitalizations are associated with poor survival outcomes, emphasizing the need for early intervention. Deep learning algorithms have shown promise in HF detection through electrocardiogram (ECG). However, their utility in ongoing HF monitoring remains uncertain. This study developed a deep learning model using 12-lead ECGs collected at 2 different time points to evaluate HF status changes, aiming to enhance early intervention and continuous monitoring in various healthcare settings. METHODS AND RESULTS: We analysed 30 171 ECGs from 6531 adult patients at Kobe University Hospital. The participants were randomly assigned to training, validation, and test datasets. A Transformer-based model was developed to classify HF status into deteriorated, improved, and no-change classes based on ECG waveform signals at two different time points. Performance metrics, such as the area under the receiver operating characteristic curve (AUROC) and accuracy, were calculated, and attention mapping via gradient-weighted class activation mapping was utilized to interpret the model's decision-making ability. The patients had an average age of 64.6 years (±15.4 years) and brain natriuretic peptide of 66.3 pg/mL (24.6-175.1 pg/mL). For HF status classification, the model achieved an AUROC of 0.889 [95% confidence interval (CI): 0.879-0.898] and an accuracy of 0.871 (95% CI: 0.864-0.878). CONCLUSION: Transformer-based deep learning model demonstrated high accuracy in detecting HF status changes, highlighting its potential as a non-invasive, efficient tool for HF monitoring. The reliance of the model on ECGs reduces the need for invasive, costly diagnostics, aligning with clinical needs for accessible HF management. IRB INFORMATION: Kobe University Hospital Clinical & Translational Research Center (reference number: B220208).

  2025年05月, European heart journal. Digital health, 6(3) (3), 447 - 455, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Impaired cardiac branched-chain amino acid metabolism in a novel model of diabetic cardiomyopathy.

  Junko Asakura, Manabu Nagao, Masakazu Shinohara, Tetsuya Hosooka, Naoya Kuwahara, Makoto Nishimori, Hidekazu Tanaka, Seimi Satomi-Kobayashi, Sho Matsui, Tsutomu Sasaki, Tadahiro Kitamura, Hiromasa Otake, Tatsuro Ishida, Wataru Ogawa, Ken-Ichi Hirata, Ryuji Toh

  BACKGROUND: Systemic insulin resistance plays an important role in the pathogenesis of type 2 diabetes and its complications. Although impaired branched-chain amino acid (BCAA) metabolism has been reported to be involved in the development of diabetes, the relationship between cardiac BCAA metabolism and the pathogenesis of diabetic cardiomyopathy (DbCM) remains unclear. OBJECTIVES: The aim of this study was to investigate BCAA metabolism in insulin-resistant hearts by using a novel mouse model of DbCM. METHODS: The cardiac phenotypes of adipocyte-specific 3'-phosphoinositide-dependent kinase 1 (PDK1)-deficient (A-PDK1KO) mice were assessed by histological analysis and echocardiography. The metabolic characteristics and cardiac gene expression were determined by mass spectrometry or RNA sequencing, respectively. Cardiac protein expression was evaluated by Western blot analysis. RESULTS: A-PDK1KO mouse hearts exhibited hypertrophy with prominent insulin resistance, consistent with cardiac phenotypes and metabolic disturbances previously reported as DbCM characteristics. RNA sequencing revealed the activation of BCAA uptake in diabetic hearts. In addition, the key enzymes involved in cardiac BCAA catabolism were downregulated at the protein level in A-PDK1KO mice, leading to the accumulation of BCAAs in the heart. Mechanistically, the accumulation of the BCAA leucine caused cardiac hypertrophy via the activation of mammalian target of rapamycin complex 1 (mTORC1). CONCLUSIONS: A-PDK1KO mice closely mimic the cardiac phenotypes and metabolic alterations observed in human DbCM and exhibit impaired BCAA metabolism in the heart. This model may contribute to a better understanding of DbCM pathophysiology and to the development of novel therapies for this disease.

  2025年04月, Cardiovascular diabetology, 24(1) (1), 167 - 167, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Prediction of difficulty in cryoballoon ablation with a three-dimensional deep learning model using polygonal mesh representation

  Nakasone, Kazutaka, Nishimori, Makoto, Shinohara, Masakazu, Kiuchi, Kunihiko, Takami, Mitsuru, Imamura, Kimitake, Izawa, Yu, Nakamura, Toshihiro, Sonoda, Yusuke, Takahara, Hiroyuki, Yamamoto, Kyoko, Suzuki, Yuya, Tani, Kenichi, Iwai, Hidehiro, Nakanishi, Yusuke, Hirata, Ken-ichi, Fukuzawa, Koji

  Background: Cryoballoon ablation (CBA) is useful for pulmonary vein (PV) isolation. However, some cases are challenging, requiring multiple applications and/or touch-up ablations. Although several predictors of CBA difficulty have been reported, none have assessed the spatial location and morphology of the left atrium and PVs. This study aimed to develop a three-dimensional (3D) deep learning (DL) model to predict CBA difficulty and compare its accuracy with conventional manual measurement. Methods: A 28-mm cryoballoon (Arctic Front Advance, Medtronic) was used in all cases. CBA difficulty was defined as requiring touch-up ablation and/or more than three applications per PV. We developed a DL model that can learn polygonal meshes and predict CBA difficulty. In the conventional method, predictors included a thinner left lateral ridge, higher left superior PV (LSPV) ovality index, longer LSPV ostium-bifurcation distance, and shorter right inferior PV ostium-bifurcation distance. Results: A total of 189 patients who underwent CBA for drug-resistant atrial fibrillation between January 2015 and January 2022 were included. The DL model was superior to the conventional method in accuracy (0.793 vs. 0.630, p = .042) and specificity (0.796 vs. 0.609, p = .022), with the AUC-ROC of 0.821. Conclusions: We developed a 3D DL model that can detect CBA difficulty using a polygonal mesh representation. By predicting difficult cases in advance, strategies can be developed to increase success rates.

  2025年04月, Journal of Arrhythmia, 41(2) (2), e70078, 英語

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Prediction of difficulty in cryoballoon ablation with a three-dimensional deep learning model using polygonal mesh representation.

  Kazutaka Nakasone, Makoto Nishimori, Masakazu Shinohara, Kunihiko Kiuchi, Mitsuru Takami, Kimitake Imamura, Yu Izawa, Toshihiro Nakamura, Yusuke Sonoda, Hiroyuki Takahara, Kyoko Yamamoto, Yuya Suzuki, Kenichi Tani, Hidehiro Iwai, Yusuke Nakanishi, Ken-Ichi Hirata, Koji Fukuzawa

  BACKGROUND: Cryoballoon ablation (CBA) is useful for pulmonary vein (PV) isolation. However, some cases are challenging, requiring multiple applications and/or touch-up ablations. Although several predictors of CBA difficulty have been reported, none have assessed the spatial location and morphology of the left atrium and PVs. This study aimed to develop a three-dimensional (3D) deep learning (DL) model to predict CBA difficulty and compare its accuracy with conventional manual measurement. METHODS: A 28-mm cryoballoon (Arctic Front Advance, Medtronic) was used in all cases. CBA difficulty was defined as requiring touch-up ablation and/or more than three applications per PV. We developed a DL model that can learn polygonal meshes and predict CBA difficulty. In the conventional method, predictors included a thinner left lateral ridge, higher left superior PV (LSPV) ovality index, longer LSPV ostium-bifurcation distance, and shorter right inferior PV ostium-bifurcation distance. RESULTS: A total of 189 patients who underwent CBA for drug-resistant atrial fibrillation between January 2015 and January 2022 were included. The DL model was superior to the conventional method in accuracy (0.793 vs. 0.630, p = .042) and specificity (0.796 vs. 0.609, p = .022), with the AUC-ROC of 0.821. CONCLUSIONS: We developed a 3D DL model that can detect CBA difficulty using a polygonal mesh representation. By predicting difficult cases in advance, strategies can be developed to increase success rates.

  2025年04月, Journal of arrhythmia, 41(2) (2), e70078, 英語, 国内誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• ACLY Promotes Cardiac Fibrosis via the Regulation of DNL and Histone Acetylation

  Naoya Kuwahara, Manabu Nagao, Masakazu Shinohara, Kenta Kaneshiro, Takuo Emoto, Takeshi Yoshida, Terunobu Fukuda, Makoto Nishimori, Seimi Satomi-Kobayashi, Hiromasa Otake, Ken-Ichi Hirata, Tatsuro Ishida, Ryuji Toh

  BACKGROUND: ATP citrate lyase (ACLY) is a key enzyme in de novo lipogenesis that generates acetyl-CoA from citrate. Although fatty acids are required for energy production and biomass synthesis in the heart, the regulatory mechanisms of ACLY-mediated de novo lipogenesis in pathological cardiac fibroblasts remain unknown. The aim of this study was to investigate the biological role of ACLY in cardiac remodeling. METHODS: Adeno-associated virus serotype 9-mediated shRNA targeting Acly was intravenously injected into C57BL/6J male mice. The mice were subsequently continuously infused with a mixture of angiotensin II and phenylephrine. Cardiac phenotypes were evaluated via histological staining. Cell proliferation assays, stable isotope tracing with 13C-labeled glucose, and chromatin immunoprecipitation assays were performed using human cardiac fibroblasts. RESULTS: ACLY expression was upregulated in the heart sections of mice treated with angiotensin II/phenylephrine, in particular in fibrotic areas. Masson trichrome staining revealed that Acly gene silencing significantly reduced cardiac fibrosis in these mice. Both siRNA-mediated ACLY knockdown and pharmacological ACLY inhibition suppressed the proliferation and expression of fibrous proteins in cultured human cardiac fibroblasts stimulated with transforming growth factor-β. Mechanistically, ACLY inhibition reduced de novo lipogenesis, limiting the fatty acid supply essential for cellular growth and proliferation. It also decreased H3K9 and H3K27 acetylation, in addition to the presence of acetylated H3K9 and H3K27 at the promoter regions of fibrotic genes. CONCLUSIONS: Our findings demonstrate that ACLY plays an important role in maladaptive cardiac fibrosis. ACLY could be a novel therapeutic target to prevent the development of heart failure.

  Ovid Technologies (Wolters Kluwer Health), 2025年03月, Hypertension, 英語, 国際誌

  研究論文（学術雑誌）


• Multimodal deep learning model for enhanced early detection of aortic stenosis integrating ECG and chest x-ray with cooperative learning.

  Shun Nagai, Makoto Nishimori, Masakazu Shinohara, Hidekazu Tanaka, Hiromasa Otake

  BACKGROUND: Aortic stenosis (AS) is diagnosed by echocardiography, the current gold standard, but examinations are often performed only after symptoms emerge, highlighting the need for earlier detection. Recently, artificial intelligence (AI)-based screening using non-invasive and widely available modalities such as electrocardiography (ECG) and chest x-ray(CXR) has gained increasing attention for valvular heart disease. However, single-modality approaches have inherent limitations, and in clinical practice, multimodality assessment is common. In this study, we developed a multimodal AI model integrating ECG and CXR within a cooperative learning framework to evaluate its utility for earlier detection of AS. METHODS: We retrospectively analyzed 23,886 patient records from 7,483 patients who underwent ECG, CXR, and echocardiography. A multimodal model was developed by combining a 1D ResNet50-Transformer architecture for ECG data with an EfficientNet-based architecture for CXR. Cooperative learning was implemented using a loss function that allowed the ECG and CXR models to refine each other's predictions. We split the dataset into training, validation, and test sets, and performed 1,000 bootstrap iterations to assess model stability. AS was defined echocardiographically as peak velocity ≥2.5 m/s, mean pressure gradient ≥20 mmHg, or aortic valve area ≤1.5 cm2. RESULTS: Among 7,483 patients, 608 (8.1%) were diagnosed with AS. The multimodal model achieved a test AUROC of 0.812 (95% CI: 0.792-0.832), outperforming the ECG model (0.775, 95% CI: 0.753-0.796) and the CXR model (0.755, 95% CI: 0.732-0.777). Visualization techniques (Grad-CAM, Transformer attention) highlighted distinct yet complementary features in AS patients. CONCLUSIONS: The multimodal AI model via cooperative learning outperformed single-modality methods in AS detection and may aid earlier diagnosis and reduce clinical burden.

  2025年, Frontiers in radiology, 5, 1698680 - 1698680, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Deep-learning-driven optical coherence tomography analysis for cardiovascular outcome prediction in patients with acute coronary syndrome.

  Tomoyo Hamana, Makoto Nishimori, Satoki Shibata, Hiroyuki Kawamori, Takayoshi Toba, Takashi Hiromasa, Shunsuke Kakizaki, Satoru Sasaki, Hiroyuki Fujii, Yuto Osumi, Seigo Iwane, Tetsuya Yamamoto, Shota Naniwa, Yuki Sakamoto, Yuta Fukuishi, Koshi Matsuhama, Hiroshi Tsunamoto, Hiroya Okamoto, Kotaro Higuchi, Tatsuya Kitagawa, Masakazu Shinohara, Koji Kuroda, Masamichi Iwasaki, Amane Kozuki, Junya Shite, Tomofumi Takaya, Ken-Ichi Hirata, Hiromasa Otake

  AIMS: Optical coherence tomography (OCT) can identify high-risk plaques indicative of worsening prognosis in patients with acute coronary syndrome (ACS). However, manual OCT analysis has several limitations. In this study, we aim to construct a deep-learning model capable of automatically predicting ACS prognosis from patient OCT images following percutaneous coronary intervention (PCI). METHODS AND RESULTS: Post-PCI OCT images from 418 patients with ACS were input into a deep-learning model comprising a convolutional neural network (CNN) and transformer. The primary endpoint was target vessel failure (TVF). Model performances were evaluated using Harrell's C-index and compared against conventional models based on human observation of quantitative (minimum lumen area, minimum stent area, average reference lumen area, stent expansion ratio, and lesion length) and qualitative (irregular protrusion, stent thrombus, malapposition, major stent edge dissection, and thin-cap fibroatheroma) factors. GradCAM activation maps were created after extracting attention layers by using the transformer architecture. A total of 60 patients experienced TVF during follow-up (median 961 days). The C-index for predicting TVF was 0.796 in the deep-learning model, which was significantly higher than that of the conventional model comprising only quantitative factors (C-index: 0.640) and comparable to that of the conventional model, including both quantitative and qualitative factors (C-index: 0.789). GradCAM heat maps revealed high activation corresponding to well-known high-risk OCT features. CONCLUSION: The CNN and transformer-based deep-learning model enabled fully automatic prognostic prediction in patients with ACS, with a predictive ability comparable to a conventional survival model using manual human analysis. CLINICAL TRIAL REGISTRATION: The study was registered in the University Hospital Medical Information Network Clinical Trial Registry (UMIN000049237).

  2024年11月, European heart journal. Digital health, 5(6) (6), 692 - 701, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Enhancing origin prediction: deep learning model for diagnosing premature ventricular contractions with dual-rhythm analysis focused on cardiac rotation.

  Kazutaka Nakasone, Makoto Nishimori, Masakazu Shinohara, Mitsuru Takami, Kimitake Imamura, Taku Nishida, Akira Shimane, Yasushi Oginosawa, Yuki Nakamura, Yasuteru Yamauchi, Ryudo Fujiwara, Hiroyuki Asada, Akihiro Yoshida, Kaoru Takami, Tomomi Akita, Takayuki Nagai, Philipp Sommer, Mustapha El Hamriti, Hiroshi Imada, Luigi Pannone, Andrea Sarkozy, Gian Battista Chierchia, Carlo de Asmundis, Kunihiko Kiuchi, Ken-Ichi Hirata, Koji Fukuzawa

  AIMS: Several algorithms can differentiate inferior axis premature ventricular contractions (PVCs) originating from the right side and left side on 12-lead electrocardiograms (ECGs). However, it is unclear whether distinguishing the origin should rely solely on PVC or incorporate sinus rhythm (SR). We compared the dual-rhythm model (incorporating both SR and PVC) to the PVC model (using PVC alone) and quantified the contribution of each ECG lead in predicting the PVC origin for each cardiac rotation. METHODS AND RESULTS: This multicentre study enrolled 593 patients from 11 centres-493 from Japan and Germany, and 100 from Belgium, which were used as the external validation data set. Using a hybrid approach combining a Resnet50-based convolutional neural network and a transformer model, we developed two variants-the PVC and dual-rhythm models-to predict PVC origin. In the external validation data set, the dual-rhythm model outperformed the PVC model in accuracy (0.84 vs. 0.74, respectively; P < 0.01), precision (0.73 vs. 0.55, respectively; P < 0.01), specificity (0.87 vs. 0.68, respectively; P < 0.01), area under the receiver operating characteristic curve (0.91 vs. 0.86, respectively; P = 0.03), and F1-score (0.77 vs. 0.68, respectively; P = 0.03). The contributions to PVC origin prediction were 77.3% for PVC and 22.7% for the SR. However, in patients with counterclockwise rotation, SR had a greater contribution in predicting the origin of right-sided PVC. CONCLUSION: Our deep learning-based model, incorporating both PVC and SR morphologies, resulted in a higher prediction accuracy for PVC origin, considering SR is particularly important for predicting right-sided origin in patients with counterclockwise rotation.

  2024年10月, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, 26(10) (10), 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Assessment of transthyretin instability in patients with wild-type transthyretin amyloid cardiomyopathy

  Takuya Iino, Manabu Nagao, Hidekazu Tanaka, Sachiko Yoshikawa, Junko Asakura, Makoto Nishimori, Masakazu Shinohara, Amane Harada, Shunsuke Watanabe, Tatsuro Ishida, Ken-ichi Hirata, Ryuji Toh

  2024年09月, SCIENTIFIC REPORTS, 14(1) (1), 20508 - 20508, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Anterior Atlas Fracture After C1 Laminectomy Which Was Successfully Treated by Brace Therapy: A Case Report.

  Yasushi Fujiwara, Takahiro Harada, Shinji Kotaka, Ryo Ohta, Makoto Nishimori, Nobuo Adachi

  CASE: We report a case of a 67-year-old male patient who underwent a C1 laminectomy with laminoplasty at C2-3 because of cervical ossification of the posterior longitudinal ligament. At 6 weeks after surgery, neck pain occurred after minor trauma without neurological deterioration. Computed tomography (CT) demonstrated C1 anterior atlas fracture with a 3-mm gap. After a 3-month brace therapy using a Philadelphia collar, the patient's neck pain disappeared with complete bone union according to the CT. CONCLUSION: Among 14 cases that were reported previously, none of the adult patients achieved bone union by brace therapy. Therefore, this is the only case report in which bone union could be achieved by brace therapy.

  2021年07月, JBJS case connector, 11(3) (3), 英語, 国際誌

  研究論文（学術雑誌）


• The Seven-Color TcMsEP Grading System: A Novel Alarm Method for Intraoperative Neurophysiological Monitoring Using Transcranial Electrical Stimulated Muscle Evoked Potentials (TcMsEPs) in Intramedullary Spinal Cord Tumor Surgeries.

  Yasushi Fujiwara, Shinji Kotaka, Ryo Ohta, Yasuo Arakawa, Yutaka Kadonishi, Makoto Nishimori, Hideki Manabe, Nobuo Adachi

  INTRODUCTION: Surgeons need precise information about motor deterioration risk during surgery for intramedullary spinal cord tumors (IMSCTs). However, the conventional TcMsEP alarm criterion provides limited information with a less than or a more than single alarm criterion without any grades in between, resulting in false-negative and false-positive outcomes. Therefore, we developed a "seven-color TcMsEP grading system" for neuromonitoring to provide more graded information. This study investigates the system's efficacy. METHODS: This study included 60 patients that underwent resection surgeries for IMSCTs. TcMsEP outcomes were classified into seven grades: Grade "D-0 Green" includes a wave amplitude decrease of 0%-50% compared with the baseline amplitude. Grade "D-1 Lime" includes a 50%-70% decrease. Grade "D-2 Yellow" includes a 70%-90% decrease. Grade "D-3 Orange" includes a more than 90% decrease with a clearly visible waveform. Grade "D-4 Red" includes a minimal and abnormally shaped wave. The severest, grade "D-5 Black," includes a wave that has completely disappeared. The additional grade "D-X Gray" includes cases in which the baseline wave is undetectable. Postoperative motor deterioration was evaluated in the upper limbs (PUMD) and lower limbs (PLMD) individually. RESULTS: PLMD only occurred in cases with more than a 90% wave amplitude decrease (from D-3 to D-5) and with the undetectable baseline wave (D-X). The PLMD rate increased according to the severity of the amplitude decreases (29% in D-3, 67% in D-4, 80% in D-5). Most PUMD occurred in cases with more than a 90% decrease, but one case with grade D1 had PUMD. CONCLUSIONS: The seven-color graded alarm criterion supports surgeons' decisions on how to treat the wave amplitude decrease during surgery. It provides motor deterioration risk in each grade without false negatives. Moreover, the corresponding colors enable quick comprehension of the risks.

  2021年, Spine surgery and related research, 5(4) (4), 238 - 243, 英語, 国内誌

  研究論文（学術雑誌）


• Perception of the risk of sexual transmission of HIV among Congolese and Japanese university students.

  Nlandu Roger Ngatu, Ryoji Hirota, Masamitsu Eitoku, Basilua Andre Muzembo, Makoto Nishimori, Manatsu Kuramochi, Shuhei Shintani, Shin Inoue, Ruriko Takiuchi, Marina Maegawa, Daniel Ribble, Muaka Anselme Mbenza, Nani-Tuma Hippolyte Situakibanza, Pita Damien Mbanzulu, Narufumi Suganuma

  OBJECTIVE: Sub-Saharan Africa remains the region most heavily affected by HIV infection. This study aimed to evaluate the knowledge, attitudes, and practices of Congolese students of risk behaviors for sexual transmission of HIV in comparison with their Japanese counterparts. METHODS: Of the 1,747 undergraduate students who participated in the survey, there were 1,326 respondents (752 Japanese, 574 Congolese) who voluntarily and fully filled out the auto-administered questionnaire. RESULTS: The proportion of Congolese respondents who do not always use condoms with an occasional sex partner was significantly higher, 57%, as compared with their Japanese counterparts (15%; p < 0.001). Fewer than 40% (9.9-39.7%) of Congolese respondents had accurate knowledge about multiple sex partnership (MSP), men sex with men (MSM), precocious sex, and commercial sex work (CSW) being high-risk behaviors (p < 0.001) for the sexual transmission of HIV infection. However, the proportion of Congolese tested or willing to get tested for HIV was significantly higher (97.2%) than that in the Japanese group (72.4%, p < 0.001). In Congolese students, we observed an absence of adherence to preventive measures such as condom use with an occasional sex partner, and a greater proportion of students having inaccurate knowledge of major risk behaviors such as MSM, precocious sex, and MSP, compared with their Japanese counterparts. CONCLUSIONS: This study showed that, though sexual contact remains the main mode of HIV transmission in the region, Congolese students tend to have inaccurate knowledge of risk behaviors that expose people to the sexual transmission of HIV. This suggests that continuous education targeting those risk behaviors is of great importance to reduce the spread of the HIV epidemic.

  2012年03月, Environmental health and preventive medicine, 17(2) (2), 139 - 46, 英語, 国内誌

  研究論文（学術雑誌）

• Impaired Cholesterol Uptake Capacity in Patients with Hypertriglyceridemia and Diabetes Mellitus.

  Yutaro Seto, Manabu Nagao, Takuya Iino, Amane Harada, Katsuhiro Murakami, Keiko Miwa, Masakazu Shinohara, Makoto Nishimori, Sachiko Yoshikawa, Junko Asakura, Tomoo Fujioka, Tatsuro Ishida, Ken-Ichi Hirata, Ryuji Toh

  BACKGROUND: Although low high-density lipoprotein cholesterol (HDL-C) levels are a common metabolic abnormality associated with insulin resistance, their role in cardiovascular risk stratification remains controversial. Recently, we developed a simple, high-throughput, cell-free assay system to evaluate the "cholesterol uptake capacity (CUC)" as a novel concept for HDL functionality. In this study, we assessed the CUC in patients with hypertriglyceridemia and diabetes mellitus. METHODS: The CUC was measured using cryopreserved serum samples from 285 patients who underwent coronary angiography or percutaneous coronary intervention between December 2014 and May 2019 at Kobe University Hospital. RESULTS: The CUC was significantly lower in diabetic patients (n = 125) than in nondiabetic patients (93.0 vs 100.7 arbitrary units (A.U.), P = 0.002). Patients with serum triglyceride (TG) levels >150 mg/dL (n = 94) also had a significantly lower CUC (91.8 vs 100.0 A.U., P = 0.004). Furthermore, the CUC showed a significant inverse correlation with TG, hemoglobin A1c (Hb A1c), homeostasis model assessment of insulin resistance (HOMA-IR), and body mass index (BMI). Finally, the HDL-C/Apolipoprotein A1 (ApoA1) ratio, calculated as a surrogate index of HDL particle size, was significantly positively correlated with the CUC (r2 = 0.49, P < 0.001), but inversely correlated with TG levels (r2 = -0.30, P < 0.001). CONCLUSIONS: The CUC decreased in patients with hypertriglyceridemia and diabetes mellitus, and HDL particle size was a factor defining the CUC and inversely correlated with TG levels, suggesting that impaired CUC in insulin-resistant states was partially due to the shift in HDL towards smaller particles. These findings provide a better understanding of the mechanisms underlying impaired HDL functionality.

  2024年07月01日, The journal of applied laboratory medicine, 9(4) (4), 728 - 740, 英語, 国際誌


• Left Ventricular Longitudinal Myocardial Function of Heart Failure Patients With Transition From Reduced to Preserved Ejection Fraction and of Those With Preserved Ejection Fraction.

  Shun Nagai, Makoto Nishimori, Masayuki Kintsu, Saki Todo, Eri Ota, Susumu Odajima, Kimikazu Takeuchi, Yasushi Ichikawa, Yuki Yamauchi, Hiroaki Shiraki, Kentaro Yamashita, Terunobu Fukuda, Eriko Hisamatsu, Ken-Ichi Hirata, Hidekazu Tanaka

  Background: Left ventricular (LV) longitudinal myocardial function is associated with the outcomes of heart failure (HF) patients. HF with improved ejection fraction (EF), known as HFimpEF, which is defined as current LVEF >40% but any previously documented LVEF ≤40%, has favorable outcomes compared with HF with preserved EF (HFpEF). However, LV longitudinal myocardial function in patients with previously reduced LVEF (<50%) but improved LVEF to within the normal range (≥50%) (HFnorEF) and its association with cardiovascular events remain unclear. Methods and Results: We studied 70 patients with HFpEF and 65 with HFnorEF. LV longitudinal myocardial function was assessed as global longitudinal strain (GLS). The primary endpoint was defined as cardiovascular death or HF hospitalization during follow-up of 5.6±3.1 years. The GLS of HFpEF patients was significantly lower than that of HFnorEF patients (13.6±3.5% vs. 14.8±2.2%, P=0.02) even when the LVEF was similar. Multivariate Cox proportional hazards analysis showed that GLS was independently associated with cardiovascular events. Furthermore, of the entire study population, patients with GLS >15.0% had fewer cardiovascular events than those without (log-rank P=0.014) among all the patients. Conclusions: LV longitudinal myocardial dysfunction was more frequently observed in patients with HFpEF than in those with HFnorEF, even when LVEF was similar, and was independently associated with cardiovascular events for HF patients with current LVEF ≥50%.

  2024年05月10日, Circulation reports, 6(5) (5), 161 - 167, 英語, 国内誌

  神戸大学リポジトリ（Kernel）へのリンク


• Scoring System for Prediction of Left Ventricular Longitudinal Myocardial Dysfunction in Preclinical Heart Failure Patients.

  Susumu Odajima, Makoto Nishimori, Hiroshi Okamoto, Ken-Ichi Hirata, Hidekazu Tanaka

  BACKGROUND: Detection of left ventricular (LV) abnormalities is essential for patients with preclinical heart failure (HF) to delay progression to clinical HF. Global longitudinal strain (GLS) is a sensitive marker for the early occurrence of subtle abnormalities in LV function, but not all echocardiographic instruments can measure GLS.Methods and Results: We studied 853 preclinical HF patients to devise a scoring system for predicting low GLS (<16%). The associations of medical history and echocardiographic parameters with low GLS were evaluated using Cox proportional hazards analysis. Model 1 of the system consisted of medical history; for Model 2, conventional echocardiographic parameters were added to Model 1. For Model 1, a score ≥5 points meant prediction of low GLS with 90.2% sensitivity and 62.9% specificity (male=1 point, hypertension=4 points, dyslipidemia=1 point, atrial fibrillation=2 points, history of cardiac surgery=2 points). For Model 2, a score ≥4 points denotes prediction of low GLS with 80.3% sensitivity and 76.5% specificity (male=1 point, hypertension=2 points, atrial fibrillation=2 points, LV mass index >116 g/m2[male] or >96 g/m2[female]=1 point, LV ejection fraction <59%=2 points, E/e' >14=1 point). CONCLUSIONS: Our scoring system provides an easy-to-use evaluation of LV longitudinal myocardial dysfunction, and may prove useful for risk stratification of patients with preclinical HF.

  2024年04月25日, Circulation journal : official journal of the Japanese Circulation Society, 88(5) (5), 703 - 710, 英語, 国内誌

  神戸大学リポジトリ（Kernel）へのリンク


• Stress-induced stenotic vascular remodeling via reduction of plasma omega-3 fatty acid metabolite 4-oxoDHA by noradrenaline.

  Makoto Nishimori, Naomi Hayasaka, Kazunori Otsui, Nobutaka Inoue, Junko Asakura, Manabu Nagao, Ryuji Toh, Tatsuro Ishida, Ken-Ichi Hirata, Tomoyuki Furuyashiki, Masakazu Shinohara

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

  2024年02月20日, Scientific reports, 14(1) (1), 4178 - 4178, 英語, 国際誌

  神戸大学リポジトリ（Kernel）へのリンク


• Left ventricular reverse remodeling following initiation of sacubitril/valsartan for heart failure with reduced ejection fraction and low blood pressure.

  Yu Nishihara, Makoto Nishimori, Takuma Sawa, Koya Uemura, Shun Nagai, Saki Todo, Eri Oota, Susumu Odajima, Kimikazu Takeuchi, Yasushi Ichikawa, Masayuki Kintsu, Yuki Yamauchi, Hiroaki Shiraki, Kentaro Yamashita, Terunobu Fukuda, Eriko Hisamatsu, Masatoshi Shimizu, Ken-Ichi Hirata, Hidekazu Tanaka

  Sacubitril/valsartan has become an important first-line drug for symptomatic heart failure (HF) patients, especially with left ventricular (LV) ejection fraction (LVEF) < 50%. However, the impact of sacubitril/valsartan on cardiovascular outcomes, especially LV reverse remodeling for such patients with low blood pressure, remains uncertain. We retrospectively studied 164 HF patients with LVEF < 50% who were treated with sacubitril/valsartan from two institutions. Echocardiography was performed before and 9.5 ± 5.1 months after initiation of maximum tolerated dose of sacubitril/valsartan. The maximum tolerated dose of sacubitril/valsartan was lower for the low blood pressure group (≤ 100 mmHg in systole) than for the non-low blood pressure group (> 100 mmHg in systole) (165 ± 106 mg vs. 238 ± 124 mg, P = 0.017). As expected, significant LV reverse remodeling was observed in the non-low blood pressure group after initiation of sacubitril/valsartan. It was noteworthy that significant LV reverse remodeling was also observed in the low blood pressure group after initiation of sacubitril/valsartan (LV end-diastolic volume: 177.3 ± 66.0 mL vs. 137.7 ± 56.1 mL, P < 0.001, LV end-systolic volume: 131.6 ± 60.3 mL vs. 94.6 ± 55.7 mL, P < 0.001, LVEF: 26.8 ± 10.3% vs. 33.8 ± 13.6%, P = 0.015). Relative changes in LV volumes and LVEF after initiation of sacubitril/valsartan were similar for the two groups. In conclusion, significant LV reverse remodeling occurred after initiation of sacubitril/valsartan, even in HF patients with LVEF < 50% and systolic blood pressure ≤ 100 mmHg.

  2024年02月, Heart and vessels, 39(2) (2), 95 - 104, 英語, 国内誌

  神戸大学リポジトリ（Kernel）へのリンク


• Author Correction: Accelerated preprocessing of large numbers of brain images by parallel computing on supercomputers.

  Takehiro Jimbo, Hidetoshi Matsuo, Yuya Imoto, Takumi Sodemura, Makoto Nishimori, Yoshinari Fukui, Takuya Hayashi, Tomoyuki Furuyashiki, Ryoichi Yokoyama

  2024年01月26日, Scientific reports, 14(1) (1), 2233 - 2233, 英語, 国際誌


• ABCG5遺伝子のヘテロ接合性病原性変異による高コレステロール血症

  藤岡知夫, 石田達郎, 小林成美, 篠原正和, 西森誠, 長尾学, 吉川祥子, 飯野琢也, 朝倉絢子, 瀬戸悠太郎, 桑原直也, 多田隼人, 小島信子, 高村雅之, 平田健一, 杜隆嗣

  2024年, 日本循環器学会学術集会(Web), 88th


• Association Between Serum 3-Hydroxyisobutyric Acid and Prognosis in Patients With Chronic Heart Failure - An Analysis of the KUNIUMI Registry Chronic Cohort.

  Wataru Fujimoto, Manabu Nagao, Makoto Nishimori, Masakazu Shinohara, Makoto Takemoto, Koji Kuroda, Soichiro Yamashita, Junichi Imanishi, Masamichi Iwasaki, Takafumi Todoroki, Masanori Okuda, Hidekazu Tanaka, Tatsuro Ishida, Ryuji Toh, Ken-Ichi Hirata

  BACKGROUND: Diabetes increases the risk of heart failure (HF). 3-Hydroxyisobutyric acid (3-HIB) is a muscle-derived metabolite reflecting systemic insulin resistance. In this study, we investigated the prognostic impact of 3-HIB in patients with chronic HF.Methods and Results: The KUNIUMI Registry chronic cohort is a community-based cohort study of chronic HF in Awaji Island, Japan. We analyzed the association between serum 3-HIB concentrations and adverse cardiovascular (CV) events in 784 patients from this cohort. Serum 3-HIB concentrations were significantly higher in patients with than without diabetes (P=0.0229) and were positively correlated with several metabolic parameters. According to Kaplan-Meier analysis, rates of CV death and HF hospitalization at 2 years were significantly higher among HF patients without diabetes in the high 3-HIB group (3-HIB concentrations above the median; i.e., >11.30 μmol/L) than in the low 3-HIB group (log-rank P=0.0151 and P=0.0344, respectively). Multivariable Cox proportional hazard models adjusted for established risk factors for HF revealed high 3-HIB as an independent predictor of CV death (hazard ratio [HR] 1.82; 95% confidence interval [CI] 1.16-2.85; P=0.009) and HF hospitalization (HR 1.72; 95% CI 1.17-2.53, P=0.006) in HF patients without diabetes, whereas no such trend was seen in subjects with diabetes. CONCLUSIONS: In a community cohort, circulating 3-HIB concentrations were associated with prognosis in chronic HF patients without diabetes.

  2023年12月25日, Circulation journal : official journal of the Japanese Circulation Society, 88(1) (1), 110 - 116, 英語, 国内誌

  神戸大学リポジトリ（Kernel）へのリンク


• Plasma cystine/methionine ratio is associated with left ventricular diastolic function in patients with heart disease.

  Junko Asakura, Manabu Nagao, Masakazu Shinohara, Makoto Nishimori, Sachiko Yoshikawa, Takuya Iino, Yutaro Seto, Hidekazu Tanaka, Seimi Satomi-Kobayashi, Tatsuro Ishida, Ken-Ichi Hirata, Ryuji Toh

  Elevated circulating homocysteine (Hcy) is a well-known risk factor for cardiovascular diseases (CVDs), including coronary artery disease (CAD) and heart failure (HF). It remains unclear how Hcy and its derivatives relate to left ventricular (LV) diastolic function. The aim of the present study was to investigate the relationship between plasma Hcy-related metabolites and diastolic dysfunction (DD) in patients with heart disease (HD). A total of 62 HD patients with preserved LV ejection fraction (LVEF ≥ 50%) were enrolled. Plasma Hcy and its derivatives were measured by liquid chromatography‒mass spectrometry (LC-MS/MS). Spearman's correlation test and multiple linear regression models were used to analyze the associations between metabolite levels and LV diastolic function. The cystine/methionine (CySS/Met) ratio was positively correlated with LV diastolic function, which was defined from the ratio of mitral inflow E and mitral e' annular velocities (E/e') (Spearman's r = 0.43, p < 0.001). When the subjects were categorized into two groups by E/e', the high-E/e' group had a significantly higher CySS/Met ratio than the low-E/e' group (p = 0.002). Multiple linear regression models revealed that the CySS/Met ratio was independently associated with E/e' after adjustment for age, sex, body mass index (BMI), diabetes mellitus, hypertension, chronic kidney disease (CKD), hemoglobin, and lipid peroxide (LPO) {standardized β (95% CI); 0.14 (0.04-0.23); p = 0.005}. Hcy, CySS, and Met did not show a significant association with E/e' in the same models. A high plasma CySS/Met ratio reflected DD in patients with HD.

  2023年12月, Heart and vessels, 38(12) (12), 1422 - 1430, 英語, 国内誌

  神戸大学リポジトリ（Kernel）へのリンク


• Accelerated preprocessing of large numbers of brain images by parallel computing on supercomputers.

  Takehiro Jimbo, Hidetoshi Matsuo, Yuya Imoto, Takumi Sodemura, Makoto Nishimori, Yoshinari Fukui, Takuya Hayashi, Tomoyuki Furuyashiki, Ryoichi Yokoyama

  "Preprocessing" is the first step required in brain image analysis that improves the overall quality and reliability of the results. However, it is computationally demanding and time-consuming, particularly to handle and parcellate complicatedly folded cortical ribbons of the human brain. In this study, we aimed to shorten the analysis time for data preprocessing of 1410 brain images simultaneously on one of the world's highest-performing supercomputers, "Fugaku." The FreeSurfer was used as a benchmark preprocessing software for cortical surface reconstruction. All the brain images were processed simultaneously and successfully analyzed in a calculation time of 17.33 h. This result indicates that using a supercomputer for brain image preprocessing allows big data analysis to be completed shortly and flexibly, thus suggesting the possibility of supercomputers being used for expanding large data analysis and parameter optimization of preprocessing in the future.

  2023年11月14日, Scientific reports, 13(1) (1), 19901 - 19901, 英語, 国際誌


• Identification of factors associated with progression of left atrial enlargement in patients with atrial fibrillation.

  Koya Uemura, Makoto Nishimori, Shun Nagai, Mariko Takeuchi, Yu Nishihara, Saki Todo, Eri Oota, Susumu Odajima, Kimikazu Takeuchi, Yasushi Ichikawa, Masayuki Kintsu, Yuki Yamauchi, Hiroaki Shiraki, Kentaro Yamashita, Terunobu Fukuda, Eriko Hisamatsu, Ken-Ichi Hirata, Hidekazu Tanaka

  Left atrial (LA) enlargement frequently occurs in atrial fibrillation (AF) patients, and this enlargement is associated with the development of heart failure, thromboembolism, or atrial functional mitral regurgitation (AFMR). AF patients can develop LA enlargement over time, but its progression depends on the individual. So far, the factors that cause progressive LA enlargement in AF patients have thus not been elucidated, so that the aim of this study was to identify the factors associated with the progression of LA enlargement in AF patients. We studied 100 patients with persistent or permanent AF (aged: 67 ± 2 years, 40 females). Echocardiography was performed at baseline and 12 (5-30) months after follow-up. LA size was evaluated as the LA volume index which was calculated with the biplane modified Simpson's method from apical four-and two-chamber views, and then normalized to the body surface area (LAVI). The deterioration of AFMR after follow-up was defined as a deterioration in severity of mitral regurgitation (MR) by a grade of 1 or more. Multivariate regression analysis demonstrated that hypertension (p = .03) was an independently associated parameter of progressive LA enlargement, as was baseline LAVI. In addition, the Kaplan-Meier curve indicated that patients with hypertension tended to show greater deterioration of AFMR after follow-up than those without hypertension (log-rank p = .08). Hypertension proved to be strongly associated with progression of LA enlargement over time in patients with AF. Our findings provide new insights for better management of patients with AF to prevent the development of AFMR.

  2023年09月, Echocardiography (Mount Kisco, N.Y.), 40(9) (9), 976 - 982, 英語, 国際誌

  神戸大学リポジトリ（Kernel）へのリンク


• Prediction of the debulking effect of rotational atherectomy using optical frequency domain imaging: a prospective study.

  Tomoyo Hamana, Hiroyuki Kawamori, Takayoshi Toba, Makoto Nishimori, Kosuke Tanimura, Shunsuke Kakizaki, Koichi Nakamura, Daichi Fujimoto, Satoru Sasaki, Yuto Osumi, Masayoshi Fujii, Seigo Iwane, Tetsuya Yamamoto, Shota Naniwa, Yuki Sakamoto, Yuta Fukuishi, Koshi Matsuhama, Ken-Ichi Hirata, Hiromasa Otake

  This study determined the predictive accuracy of optical frequency domain imaging (OFDI) on debulking effects of rotational atherectomy (RA) and compared the predictive accuracy of OFDI catheter-based with Rota wire-based prediction methods. This prospective, single-center, observational study included 55 consecutive patients who underwent OFDI-guided RA. On pre-RA OFDI images, a circle, identical to the Rota burr was drawn at the center of the OFDI catheter (OFDI catheter-based prediction method) or wire (wire-based prediction method). The area overlapping the vessel wall was defined as the predicted ablation area (P-area). The actual ablated area (A-area) was measured by superimposing the OFDI images before and after RA. The overlapping P-area and A-area were defined as overlapped ablation area (O-area), and the predictive accuracy was evaluated by %Correct area (O-area/P-area) and %Error area (A-area  - O-area/A-area). The median %Correct and %Error areas were 47.8% and 41.6%, respectively. Irrelevant ablation (low %Correct-/high % Error areas) and over ablation (high %Correct-/high % Error areas) were related to deep vessel injury and intimal flap outside the P-area. The predictive accuracy was better in the OFDI catheter-based prediction method than the wire-based prediction method in the cross sections where the OFDI catheter and wire came in contact. However, it was better in the latter than the former where the OFDI catheter and wire were not in contact. OFDI-based simulation of the RA effect is feasible though accuracy may be affected by the OFDI catheter and wire position. OFDI-based simulation of RA effect might reduce peri-procedural complications during RA.

  2023年07月, Cardiovascular intervention and therapeutics, 38(3) (3), 316 - 326, 英語, 国内誌

  神戸大学リポジトリ（Kernel）へのリンク


• Predictors of target lesion revascularisation after drug-eluting stent implantation for calcified nodules: an optical coherence tomography study.

  Tomoyo Hamana, Hiroyuki Kawamori, Takayoshi Toba, Shunsuke Kakizaki, Koichi Nakamura, Daichi Fujimoto, Satoru Sasaki, Hiroyuki Fujii, Yuto Osumi, Tomoo Fujioka, Makoto Nishimori, Amane Kozuki, Junya Shite, Masamichi Iwasaki, Tomofumi Takaya, Ken-Ichi Hirata, Hiromasa Otake

  BACKGROUND: Evidence of prognostic factors for stent failure after drug-eluting stent implantation for calcified nodules (CNs) is limited. AIMS: We aimed to clarify the prognostic risk factors associated with stent failure among patients who underwent drug-eluting stent implantation for CN lesions using optical coherence tomography (OCT). METHODS: This retrospective, multicentre, observational study included 108 consecutive patients with CNs who underwent OCT-guided percutaneous coronary intervention (PCI). To evaluate the quality of CNs, we measured their signal intensity and analysed the degree of signal attenuation. All CN lesions were divided into dark or bright CNs according to the half width of signal attenuation, greater or lower than 332, respectively. RESULTS: During the median follow-up period of 523 days, 25 patients (23.1%) experienced target lesion revascularisation (TLR). The 5-year cumulative incidence of TLR was 32.6%. Multivariable Cox regression analysis revealed that younger age, haemodialysis, eruptive CNs, dark CNs assessed by pre-PCI OCT, disrupted fibrous tissue protrusions, and irregular protrusions assessed by post-PCI OCT were independently associated with TLR. The prevalence of in-stent CNs (IS-CNs) observed at follow-up OCT was significantly higher in the TLR group than in the non-TLR group. CONCLUSIONS: Factors such as younger age, haemodialysis, eruptive CNs, dark CNs, disrupted fibrous tissue, or irregular protrusions were independently related to TLR in patients with CNs. The high prevalence of IS-CNs might indicate that the main cause of stent failure implanted in CN lesions could be the recurrence of CN progression in the stented segment.

  2023年06月05日, EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology, 19(2) (2), e123-e133, 英語, 国際誌


• EASY-WPW: a novel ECG-algorithm for easy and reliable localization of manifest accessory pathways in children and adults.

  Mustapha El Hamriti, Martin Braun, Stephan Molatta, Guram Imnadze, Moneeb Khalaph, Philipp Lucas, Julia Kathinka Nolting, Khuraman Isgandarova, Vanessa Sciacca, Thomas Fink, Leonard Bergau, Christian Sohns, Kunihiko Kiuchi, Makoto Nishimori, Christian-Hendrik Heeger, Martin Borlich, Dong-In Shin, Sonia Busch, Denise Guckel, Philipp Sommer

  AIMS: Accessory pathway (AP) ablation is a standard procedure for the treatment of Wolff-Parkinson-White syndrome (WPW). Twelve-lead electrocardiogram (ECG)-based delta wave analysis is essential for predicting ablation sites. Previous algorithms have shown to be complex, time-consuming, and unprecise. We aimed to retrospectively develop and prospectively validate a new, simple ECG-based algorithm considering the patients' heart axis allowing for exact localization of APs in patients undergoing ablation for WPW. METHODS AND RESULTS: Our multicentre study included 211 patients undergoing ablation of a single manifest AP due to WPW between 2013 and 2021. The algorithm was developed retrospectively and validated prospectively by comparing its efficacy to two established ones (Pambrun and Arruda). All patients (32 ± 19 years old, 47% female) underwent successful pathway ablation. Prediction of AP-localization was correct in 197 patients (93%) (sensitivity 92%, specificity 99%, PPV 96%, and NPV 99%). Our algorithm was particularly useful in correctly localizing antero-septal/-lateral (sensitivity and specificity 100%) and posteroseptal (sensitivity 98%, specificity 92%) AP in proximity to the tricuspid valve. The accuracy of EASY-WPW was superior compared to the Pambrun (93% vs. 84%, P = 0.003*) and the Arruda algorithm (94% vs. 75%, P < 0.001*). A subgroup analysis of children (n = 58, 12 ± 4 years old, 55% female) revealed superiority to the Arruda algorithm (P < 0.001*). The reproducibility of our algorithm was excellent (ϰ>0.8; P < 0.001*). CONCLUSION: The novel EASY-WPW algorithm provides reliable and accurate pre-interventional ablation site determination in WPW patients. Only two steps are necessary to locate left-sided AP, and three steps to determine right-sided AP.

  2023年02月16日, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, 25(2) (2), 600 - 609, 英語, 国際誌


• 血清3-ヒドロキシイソ酪酸濃度と慢性心不全患者の予後の関連~KUNIUMI registry chronic cohortを用いた検証~

  長尾学, 藤本恒, 藤本恒, 西森誠, 篠原正和, 篠原正和, 竹本良, 黒田浩史, 山下宗一郎, 今西純一, 岩崎正道, 轟貴史, 奥田正則, 田中秀和, 杜隆嗣, 平田健一, 平田健一

  2023年, 日本動脈硬化学会総会・学術集会プログラム・抄録集(Web), 55th


• 血中cystine/methionine比とHFpEF患者における左室拡張機能との関連

  朝倉絢子, 長尾学, 篠原正和, 篠原正和, 西森誠, 吉川祥子, 飯野琢也, 田中秀和, 小林成美, 石田達郎, 平田健一, 平田健一, 杜隆嗣

  2023年, 日本腫瘍循環器学会学術集会抄録集(Web), 6th


• Development of a Visualization Deep Learning Model for Classifying Origins of Ventricular Arrhythmias.

  Kazutaka Nakasone, Makoto Nishimori, Kunihiko Kiuchi, Masakazu Shinohara, Koji Fukuzawa, Mitsuru Takami, Mustapha El Hamriti, Philipp Sommer, Jun Sakai, Toshihiro Nakamura, Atsusuke Yatomi, Yusuke Sonoda, Hiroyuki Takahara, Kyoko Yamamoto, Yuya Suzuki, Kenichi Tani, Hidehiro Iwai, Yusuke Nakanishi, Ken-Ichi Hirata

  BACKGROUND: Several algorithms have been proposed for differentiating the right and left outflow tracts (RVOT/LVOT) arrhythmia origins from 12-lead electrocardiograms (ECGs); however, the procedure is complicated. A deep learning (DL) model, a form of artificial intelligence, can directly use ECGs and depict the importance of the leads and waveforms. This study aimed to create a visualized DL model that could classify arrhythmia origins more accurately.Methods and Results: This study enrolled 80 patients who underwent catheter ablation. A convolutional neural network-based model that could classify arrhythmia origins with 12-lead ECGs and visualize the leads that contributed to the diagnosis using a gradient-weighted class activation mapping method was developed. The average prediction results of the origins by the DL model were 89.4% (88.2-90.6) for accuracy and 95.2% (94.3-96.2) for recall, which were significantly better than when a conventional algorithm is used. The ratio of the contribution to the prediction differed between RVOT and LVOT origins. Although leads V1 to V3 and the limb leads had a focused balance in the LVOT group, the contribution ratio of leads aVR, aVL, and aVF was higher in the RVOT group. CONCLUSIONS: This study diagnosed the arrhythmia origins more accurately than the conventional algorithm, and clarified which part of the 12-lead waveforms contributed to the diagnosis. The visualized DL model was convincing and may play a role in understanding the pathogenesis of arrhythmias.

  2022年07月25日, Circulation journal : official journal of the Japanese Circulation Society, 86(8) (8), 1273 - 1280, 英語, 国内誌


• Inhibition of glutaminase 1-mediated glutaminolysis improves pathological cardiac remodeling.

  Sachiko Yoshikawa, Manabu Nagao, Ryuji Toh, Masakazu Shinohara, Takuya Iino, Yasuhiro Irino, Makoto Nishimori, Hidekazu Tanaka, Seimi Satomi-Kobayashi, Tatsuro Ishida, Ken-Ichi Hirata

  Alterations in cardiac metabolism are strongly associated with the pathogenesis of heart failure (HF). We recently reported that glutamine-dependent anaplerosis, termed glutaminolysis, was activated by H2O2 stimulation in rat cardiomyocytes, which seemed to be an adaptive response by which cardiomyocytes survive acute stress. However, the molecular mechanisms and fundamental roles of glutaminolysis in the pathophysiology of the failing heart are still unknown. Here, we treated wild-type mice (C57BL/6J) and rat neonatal cardiomyocytes (RNCMs) and fibroblasts (RNCFs) with angiotensin II (ANG II) to induce pathological cardiac remodeling. Glutaminase 1 (GLS1), a rate-limiting glutaminolysis enzyme, was significantly increased in ANG II-induced mouse hearts, RNCMs and RNCFs. Unexpectedly, a GLS1 inhibitor attenuated ANG II-induced left ventricular hypertrophy and fibrosis in the mice, and gene knockdown and pharmacological perturbation of GLS1 suppressed hypertrophy and the proliferation of RNCMs and RNCFs, respectively. Using mass spectrometry (MS)-based stable isotope tracing with 13C-labeled glutamine, we observed glutamine metabolic flux in ANG II-treated RNCMs and RNCFs. The incorporation of 13C atoms into tricarboxylic acid (TCA) cycle intermediates and their derivatives was markedly enhanced in both cell types, indicating the activation of glutaminolysis in hypertrophied hearts. Notably, GLS1 inhibition reduced the production of glutamine-derived aspartate and citrate, which are required for the biosynthesis of nucleic acids and lipids, possibly contributing to the suppression of cardiac hypertrophy and fibrosis. The findings of the present study reveal that GLS1-mediated upregulation of glutaminolysis leads to maladaptive cardiac remodeling. Inhibition of this anaplerotic pathway could be a novel therapeutic approach for HF.NEW & NOTEWORTHY To our knowledge, this study is the first to demonstrate that increased GLS1 expression and subsequent activation of glutaminolysis are associated with exacerbation of cardiac hypertrophy and fibrosis. Inhibiting GLS1 antagonized the adverse cardiac remodeling in vitro and in vivo, partly due to reduction of glutamine-derived metabolites, which are necessary for cellular growth and proliferation. Increased glutamine utilization for anabolic reactions in cardiac cells may be related to the pathogenesis and development of HF.

  2022年05月01日, American journal of physiology. Heart and circulatory physiology, 322(5) (5), H749-H761, 英語, 国際誌


• AI-Assisted In-House Power Monitoring for the Detection of Cognitive Impairment in Older Adults.

  Yuriko Nakaoku, Soshiro Ogata, Shunsuke Murata, Makoto Nishimori, Masafumi Ihara, Koji Iihara, Misa Takegami, Kunihiro Nishimura

  In-home monitoring systems have been used to detect cognitive decline in older adults by allowing continuous monitoring of routine activities. In this study, we investigated whether unobtrusive in-house power monitoring technologies could be used to predict cognitive impairment. A total of 94 older adults aged ≥65 years were enrolled in this study. Generalized linear mixed models with subject-specific random intercepts were used to evaluate differences in the usage time of home appliances between people with and without cognitive impairment. Three independent power monitoring parameters representing activity behavior were found to be associated with cognitive impairment. Representative values of mean differences between those with cognitive impairment relative to those without were -13.5 min for induction heating in the spring, -1.80 min for microwave oven in the winter, and -0.82 h for air conditioner in the winter. We developed two prediction models for cognitive impairment, one with power monitoring data and the other without, and found that the former had better predictive ability (accuracy, 0.82; sensitivity, 0.48; specificity, 0.96) compared to the latter (accuracy, 0.76; sensitivity, 0.30; specificity, 0.95). In summary, in-house power monitoring technologies can be used to detect cognitive impairment.

  2021年09月17日, Sensors (Basel, Switzerland), 21(18) (18), 英語, 国際誌


• Effects of Elaidic Acid on HDL Cholesterol Uptake Capacity.

  Takuya Iino, Ryuji Toh, Manabu Nagao, Masakazu Shinohara, Amane Harada, Katsuhiro Murakami, Yasuhiro Irino, Makoto Nishimori, Sachiko Yoshikawa, Yutaro Seto, Tatsuro Ishida, Ken-Ichi Hirata

  Recently we established a cell-free assay to evaluate "cholesterol uptake capacity (CUC)" as a novel concept for high-density lipoprotein (HDL) functionality and demonstrated the feasibility of CUC for coronary risk stratification, although its regulatory mechanism remains unclear. HDL fluidity affects cholesterol efflux, and trans fatty acids (TFA) reduce lipid membrane fluidity when incorporated into phospholipids (PL). This study aimed to clarify the effect of TFA in HDL-PL on CUC. Serum was collected from 264 patients after coronary angiography or percutaneous coronary intervention to measure CUC and elaidic acid levels in HDL-PL, and in vitro analysis using reconstituted HDL (rHDL) was used to determine the HDL-PL mechanism affecting CUC. CUC was positively associated with HDL-PL levels but negatively associated with the proportion of elaidic acid in HDL-PL (elaidic acid in HDL-PL/HDL-PL ratio). Increased elaidic acid-phosphatidylcholine (PC) content in rHDL exhibited no change in particle size or CUC compared to rHDL containing oleic acid in PC. Recombinant human lecithin-cholesterol acyltransferase (LCAT) enhanced CUC, and LCAT-dependent enhancement of CUC and LCAT-dependent cholesterol esterification were suppressed in rHDL containing elaidic acid in PC. Therefore, CUC is affected by HDL-PL concentration, HDL-PL acyl group composition, and LCAT-dependent cholesterol esterification. Elaidic acid precipitated an inhibition of cholesterol uptake and maturation of HDL; therefore, modulation of HDL-PL acyl groups could improve CUC.

  2021年09月04日, Nutrients, 13(9) (9), 英語, 国際誌


• Accessory pathway analysis using a multimodal deep learning model.

  Makoto Nishimori, Kunihiko Kiuchi, Kunihiro Nishimura, Kengo Kusano, Akihiro Yoshida, Kazumasa Adachi, Yasutaka Hirayama, Yuichiro Miyazaki, Ryudo Fujiwara, Philipp Sommer, Mustapha El Hamriti, Hiroshi Imada, Makoto Takemoto, Mitsuru Takami, Masakazu Shinohara, Ryuji Toh, Koji Fukuzawa, Ken-Ichi Hirata

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

  2021年04月13日, Scientific reports, 11(1) (1), 8045 - 8045, 英語, 国際誌


• In Vivo Imaging of Venous Thrombus and Pulmonary Embolism Using Novel Murine Venous Thromboembolism Model.

  Mitsumasa Okano, Tetsuya Hara, Makoto Nishimori, Yasuhiro Irino, Seimi Satomi-Kobayashi, Masakazu Shinohara, Ryuji Toh, Farouc A Jaffer, Tatsuro Ishida, Ken-Ichi Hirata

  This work established a new murine venous thromboembolism (VTE) model. This model has multiple novel features representing clinical VTE that include the following: 1) deep venous thrombosis (DVT) was formed and extended in the long axis of femoral/saphenous vein; 2) thrombus was formed in a venous valve pocket; 3) deligation of suture-induced spontaneous pulmonary emboli of fibrin-rich DVT; and 4) cardiac motion-free femoral/saphenous vein allowed high-resolution intravital microscopic imaging of fibrin-rich DVT. This new model requires only commercially available epifluorescence microscopy. Therefore, this model has significant potential for better understanding of VTE pathophysiology.

  2020年04月, JACC. Basic to translational science, 5(4) (4), 344 - 356, 英語, 国際誌


• 酸化ストレスに対するα-ケトグルタル酸の心筋細胞保護作用

  渡部 晃一, 杜 隆嗣, 西森 誠, 岡野 光真, 入野 康宏, 原 哲也, 篠原 正和, 小林 成美, 石田 達郎, 平田 健一

  (一社)日本心臓病学会, 2019年09月, 日本心臓病学会学術集会抄録, 67回, P - 206, 日本語


• Establishment of Femoral Vein Ligation Model: a New DVT Imaging Model

  Tetsuya Hara, Mitsumasa Okano, Makoto Nishimori, Koichi Watanabe, Yasuhiro Irino, Seimi Kobayashi, Masakazu Shinohara, Ryuji Toh, Tatsuro Ishida, Ken-ichi Hirata

  2019年05月, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 39, 英語

  研究発表ペーパー・要旨（国際会議）


• HDL機能性の新しい指標であるコレステロール取り込み能とコレステロール排出能の冠動脈プラーク特性に関連した比較(Comparison of Cholesterol Uptake Capacity, a Novel Indicator for HDL-functionality, and Cholesterol Efflux Capacity in Association with Coronary Plaque Properties)

  尾下 寿彦, 杜 隆嗣, 岡野 光真, 渡部 晃一, 西森 誠, 永野 雄一朗, 原田 周, 村上 克洋, 桐山 真利亜, 吉川 景子, 三輪 桂子, 小林 成美, 篠原 正和, 原 哲也, 入野 康宏, 大竹 寛雅, 石田 達郎, 平田 健一

  (一社)日本循環器学会, 2019年03月, 日本循環器学会学術集会抄録集, 83回, PJ100 - 3, 英語


• Establishment of Novel Deep Venous Thrombosis Model Suitable for In Vivo Imaging.

  Mitsumasa Okano, Tetsuya Hara, Makoto Nishimori, Koichi Watanabe, Toshihiko Oshita, Yasuhiro Irino, Seimi Kobayashi, Masakazu Shinohara, Ryuji Toh, Tatsuro Ishida, Ken-ichi Hirata

  2018年11月06日, CIRCULATION, 138, 英語

  研究発表ペーパー・要旨（国際会議）


• Atypical inferoseptal accessory pathway connection associated with an aneurysm of the coronary sinus: Insight from a three-dimensional combined image of electroanatomic mapping and computed tomography.

  Makoto Nishimori, Kunihiko Kiuchi, Shumpei Mori, Jun Kurose, Yu Izawa, Shingo Kouno, Hiroaki Nakagawa, Shinsuke Shimoyama, Koji Fukuzawa, Ken-Ichi Hirata

  2018年09月, HeartRhythm case reports, 4(9) (9), 389 - 392, 英語, 国際誌


• Acute pulmonary edema in patients with reduced left ventricular ejection fraction is associated with concentric left ventricular geometry.

  Junichi Imanishi, Kenji Kaihotsu, Sachiko Yoshikawa, Makoto Nishimori, Naohiko Sone, Tomoyuki Honjo, Masanori Iwahashi

  Although acute pulmonary edema (APE) is common in patients with heart failure (HF) with preserved ejection fraction (EF), its pathogenesis in patients with HF with reduced EF (HFrEF) is not completely understood. The purpose of our study was to explore the contributions of left ventricular (LV) geometry to understand the difference between HFrEF patients with or without APE. We studied 122 consecutive acute decompensated HF patients with HFrEF (≤40%). APE was defined as acute-onset dyspnea and radiographic alveolar edema requiring immediate airway intervention. LV geometry was determined from a combination of the LV mass index and relative wall thickness (RWT). Long-term unfavorable outcome events were tracked during a follow-up of a median of 21 months (interquartile range, 10-28 months), during which APE was observed in 29 patients (24%). Compared to those without APE, hospitalized patients with APE had a higher systolic blood pressure, RWT, and LVEF and lower end-diastolic dimension. Among echocardiographic variables, a multivariate logistic regression analysis identified RWT as the only independent determinant of APE (hazard ratio: 2.46, p < 0.001). Those with concentric geometry (n = 25; RWT > 0.42) had a higher incidence of APE relative to those with non-concentric geometry. Furthermore, among patients with APE, mortality was significantly higher among those with concentric geometry (log-rank, p = 0.008). Compared with non-concentric geometry, concentric geometry (increased RWT, not LV mass) was strongly associated with APE onset and a poorer outcome among APE patients. An easily obtained echocardiographic RWT index may facilitate the risk stratification of patients.

  2018年02月, The international journal of cardiovascular imaging, 34(2) (2), 185 - 192, 英語, 国際誌


• 冠静脈洞瘤を合併したWPW症候群に対し,解剖学的情報がアブレーションに有用であった1例

  西森誠, 木内邦彦, 森俊平, 伊澤有, 河野慎吾, 福沢公二, 平田健一

  2018年, 日本循環器学会近畿地方会(Web), 125th


• Dasatinib-Induced Pulmonary Arterial Hypertension Treated with Upfront Combination Therapy.

  Makoto Nishimori, Tomoyuki Honjo, Kenji Kaihotsu, Naohiko Sone, Sachiko Yoshikawa, Junichi Imanishi, Kazuhiko Nakayama, Noriaki Emoto, Masanori Iwahashi

  Pulmonary arterial hypertension (PAH) is a rare complication of dasatinib that was approved as a first-line therapy for chronic myelocytic leukemia (CML). A 24-year-old man presenting dyspnea at rest and leg edema was admitted to our hospital. He had been diagnosed with CML and prescribed dasatinib for 4 years. Chest X-ray showed significant bilateral pleural effusion and heart enlargement. Echocardiography revealed interventricular septal compression and elevated peak tricuspid regurgitation pressure gradient of 66.7 mmHg indicating severe pulmonary hypertension. After the other specific diseases to provoke PAH were excluded, he was diagnosed with dasatinib-induced PAH. Despite discontinuation of dasatinib and intravenous administration of diuretic for two weeks, World Health Organization (WHO) functional class was still II and mean pulmonary arterial pressure (PAP) was high at 37 mmHg. Therefore, we administered sildenafil and bosentan together as an upfront combination therapy three weeks after dasatinib discontinuation. Six months later, his symptoms improved to WHO functional class I and mean PAP was decreased to 31 mmHg. Although PAH is a rare complication of dasatinib, symptomatic patients prescribed with dasatinib should have an echocardiogram for PAH screening. Moreover, the upfront combination therapy would be a useful option for symptomatic patients after discontinuation of dasatinib.

  2018年, Case reports in cardiology, 2018, 3895197 - 3895197, 英語, 国際誌


• Marked Thrombocytosis in Chronic Eosinophilic Pneumonia and Analysis of Cytokine Mechanism.

  Makoto Nishimori, Hiroko Tsunemine, Hayato Maruoka, Kiminari Itoh, Taiichi Kodaka, Hironori Matsuoka, Takayuki Takahashi

  A 47-year-old woman with marked thrombocytosis of 1,650 × 10(9)/L was diagnosed with chronic eosinophilic pneumonia (CEP) based on imaging of the lung and abundant eosinophils in bronchoalveolar lavage fluid. Known gene abnormalities that cause eosinophilia were not detected in bone marrow cells. Treatment with oral prednisolone at 20 mg/day relieved the CEP and resolved the laboratory abnormalities, including eosinophilia and thrombocytosis. Serum concentrations of interleukin (IL)-5 and IL-6 were elevated to 9.6 and 14.0 pg/mL, respectively. The megakaryocyte-potentiating activity of IL-6 and possibly, that of IL-1β, which is known to be secreted by activated eosinophils, may have caused the marked thrombocytosis in this patient.

  2015年, Journal of clinical and experimental hematopathology : JCEH, 55(2) (2), 97 - 102, 英語, 国内誌


• Fatal fungemia with Scedosporium prolificans in a patient with acute myeloid leukemia.

  Makoto Nishimori, Toshio Takahashi, Eiko Suzuki, Taiichi Kodaka, Nobuhiro Hiramoto, Kiminari Itoh, Hiroko Tsunemine, Kyoko Yarita, Katsuhiko Kamei, Hiroshi Takegawa, Takayuki Takahashi

  Scedosporium prolificans (S. prolificans) is a type of mold, which rarely affects immunocompromised people. We treated a 71-year-old woman with acute myeloid leukemia (AML-M5a) with low-dose cytarabine, acralubicin, and filgrastim as the induction therapy. On day 7 after the initiation of chemotherapy, she became febrile and agranulocytic, and developed anal pain ; therefore, we discontinued the chemotherapy on day 8. Broad-spectrum antibiotics, micafungin, and then liposomal amphotericin B were ineffective. The serum concentration of β-D-glucan was 525 pg/mL. She died of multiple organ failure on day 17. S. prolificans was detected from the blood culture on day 13. Physicians should consider Scedosporium spp. infection when principal antifungal agents are ineffective and fungal infection is strongly suspected.

  2014年, Medical mycology journal, 55(4) (4), E63-70, 英語, 国内誌

• 小児心臓検診用マルチモーダル人工知能(AI)モデルの開発研究

  西森 誠

  日本学術振興会, 科学研究費助成事業, 若手研究, 神戸大学, 2022年04月01日 - 2024年03月31日