Published Papers - Kusunose Kenya

非糖尿病アポリポタンパク質E欠損マウスにおいてDPP-4阻害薬vildagliptinは内皮機能障害を予防する(Vildagliptin, a DPP-4 Inhibitor, prevents endothelial dysfunction in non-diabetic apolipoprotein E-deficient mice)

アイニ・クンドゥズアイ, 福田 大受, 八木 秀介, 楠瀬 賢也, 山田 博胤, 添木 武, 佐田 政隆

日本性機能学会雑誌 ( (一社)日本性機能学会 )  34 ( 2 ) 189 - 189   2019.08 [ Peer Review Accepted ]

Type of publication: Research paper (other science council materials etc.)

野生型マウスにおいてFXaの直接阻害薬であるrivaroxabanは糖尿病誘発性内皮機能障害を抑制する(Rivaroxaban, a direct inhibitor of FXa, attenuated diabetes-induced endothelial dysfunction in wild-type mice)

Pham Tran Phuong, 福田 大受, 八木 秀介, 楠瀬 賢也, 山田 博胤, 添木 武, 島袋 充生, 佐田 政隆

日本性機能学会雑誌 ( (一社)日本性機能学会 )  34 ( 2 ) 191 - 191   2019.08 [ Peer Review Accepted ]

Type of publication: Research paper (other science council materials etc.)

Utilization of Artificial Intelligence in Echocardiography.

Kenya Kusunose, Akihiro Haga, Takashi Abe, Masataka Sata

Circulation journal : official journal of the Japanese Circulation Society   83 ( 8 ) 1623 - 1629   2019.07 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Echocardiography has a central role in the diagnosis and management of cardiovascular disease. Precise and reliable echocardiographic assessment is required for clinical decision-making. Even if the development of new technologies (3-dimentional echocardiography, speckle-tracking, semi-automated analysis, etc.), the final decision on analysis is strongly dependent on operator experience. Diagnostic errors are a major unresolved problem. Moreover, not only can cardiologists differ from one another in image interpretation, but also the same observer may come to different findings when a reading is repeated. Daily high workloads in clinical practice may lead to this error, and all cardiologists require precise perception in this field. Artificial intelligence (AI) has the potential to improve analysis and interpretation of medical images to a new stage compared with previous algorithms. From our comprehensive review, we believe AI has the potential to improve accuracy of diagnosis, clinical management, and patient care. Although there are several concerns about the required large dataset and "black box" algorithm, AI can provide satisfactory results in this field. In the future, it will be necessary for cardiologists to adapt their daily practice to incorporate AI in this new stage of echocardiography.

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冠動脈疾患に対する心外膜脂肪組織肥厚度の性別特異的影響(Gender specific impact of epicardial adipose tissue thickness on coronary artery disease)

マイマイチュクン・グリヌ, 福田 大受, 八木 秀介, 平田 有紀奈, 岩瀬 俊, 松浦 朋美, 伊勢 孝之, 楠瀬 賢也, 山口 浩司, 山田 博胤, 添木 武, 若槻 哲三, 佐田 政隆, 島袋 充生

日本抗加齢医学会総会プログラム・抄録集 ( (一社)日本抗加齢医学会 )  19回   254 - 254   2019.06 [ Peer Review Accepted ]

Type of publication: Research paper (other science council materials etc.)

A Deep Learning Approach for Assessment of Regional Wall Motion Abnormality From Echocardiographic Images.

Kusunose K, Abe T, Haga A, Fukuda D, Yamada H, Harada M, Sata M

JACC. Cardiovascular imaging   13 ( 2 Pt 1 ) 374 - 381   2019.05 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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OBJECTIVES: This study investigated whether a deep convolutional neural network (DCNN) could provide improved detection of regional wall motion abnormalities (RWMAs) and differentiate among groups of coronary infarction territories from conventional 2-dimensional echocardiographic images compared with that of cardiologists, sonographers, and resident readers. BACKGROUND: An effective intervention for reduction of misreading of RWMAs is needed. The hypothesis was that a DCNN trained using echocardiographic images would provide improved detection of RWMAs in the clinical setting. METHODS: A total of 300 patients with a history of myocardial infarction were enrolled. From this cohort, 3 groups of 100 patients each had infarctions of the left anterior descending (LAD) artery, the left circumflex (LCX) branch, and the right coronary artery (RCA). A total of 100 age-matched control patients with normal wall motion were selected from a database. Each case contained cardiac ultrasonographs from short-axis views at end-diastolic, mid-systolic, and end-systolic phases. After the DCNN underwent 100 steps of training, diagnostic accuracies were calculated from the test set. Independently, 10 versions of the same model were trained, and ensemble predictions were performed using those versions. RESULTS: For detection of the presence of WMAs, the area under the receiver-operating characteristic curve (AUC) produced by the deep learning algorithm was similar to that produced by the cardiologists and sonographer readers (0.99 vs. 0.98, respectively; p = 0.15) and significantly higher than the AUC result of the resident readers (0.99 vs. 0.90, respectively; p = 0.002). For detection of territories of WMAs, the AUC by the deep learning algorithm was similar to the AUC by the cardiologist and sonographer readers (0.97 vs. 0.95, respectively; p = 0.61) and significantly higher than the AUC by resident readers (0.97 vs. 0.83, respectively; p = 0.003). From a validation group at an independent site (n = 40), the AUC by the deep learning algorithm was 0.90. CONCLUSIONS: The present results support the possibility of using DCNN for automated diagnosis of RWMAs in the field of echocardiography.

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Toll-Like Receptor 9 Plays a Pivotal Role in Angiotensin II-Induced Atherosclerosis.

Fukuda D, Nishimoto S, Aini K, Tanaka A, Nishiguchi T, Kim-Kaneyama JR, Lei XF, Masuda K, Naruto T, Tanaka K, Higashikuni Y, Hirata Y, Yagi S, Kusunose K, Yamada H, Soeki T, Imoto I, Akasaka T, Shimabukuro M, Sata M

Journal of the American Heart Association   8 ( 7 ) e010860   2019.04 [ Peer Review Accepted ]

Type of publication: Research paper (other science council materials etc.)

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冠動脈プラーク内微小管腔構造は心外膜の脂肪組織の質と量に関連する 新鮮遺体を用いた研究(Coronary Intraplaque Microluminal Structure are Associated with the Quality and Quantity of Epicardial Adipose Tissue: A Fresh Cadaveric Study)

川端 豊, 若槻 哲三, 山口 浩司, 伊藤 浩敬, 福田 大受, 轟 貴史, 松浦 朋美, 伊勢 孝之, 楠瀬 賢也, 飛梅 威, 八木 秀介, 山田 博胤, 添木 武, 佐田 政隆

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  83回   PJ057 - 2   2019.03 [ Peer Review Accepted ]

Type of publication: Research paper (other science council materials etc.)

冠動脈プラークと脈管の血管の微小管腔構造は冠動脈の炎症に影響を与える 未固定遺体による研究(Microluminal Structures of Coronary Plaque and Vasa Vasorums Affect Coronary Inflammation: A Fresh Cadaveric Study)

伊藤 浩敬, 若槻 哲三, 山口 浩司, 福田 大受, 川端 豊, 轟 貴史, 松浦 朋美, 伊勢 孝之, 楠瀬 賢也, 飛梅 威, 八木 秀介, 山田 博胤, 添木 武, 佐田 政隆

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  83回   PJ106 - 5   2019.03 [ Peer Review Accepted ]

Type of publication: Research paper (other science council materials etc.)

Sequential speckle tracking imaging to detect early stage of cancer therapeutics-related cardiac dysfunction in a patient with breast cancer.

Saijo Y, Kusunose K, Yamada N, Yamada H, Nishio S, Hirata Y, Sata M

Journal of echocardiography   18 ( 2 ) 134 - 135   2019.02 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Adult onset of Immunoglobulin A vasculitis - A case report.

Yagi S, Endo I, Murakami T, Hida T, Yamamoto Y, Soga T, Ise T, Kusunose K, Yamaguchi K, Fukuda D, Yamada H, Soeki T, Wakatsuki T, Kawahito S, Sata M

The journal of medical investigation : JMI   66 ( 3.4 ) 344 - 346   2019 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Immunoglobulin A vasculitis (IgAV), formerly known as Henoch-Schönlein purpura, primarily occurs during childhood between the ages of 3 and 15 years and is the most common form of systemic vasculitis in children ; its occurrence in adults has been rarely reported. Such low incidence could be attributable to either under-diagnosis or misdiagnosis. Thus, not only pediatricians but also physicians should be able to diagnose IgAV accurately to manage the patients appropriately and avoid its associated complications. In addition, treatment of adult onset IgAV with renal involvement has not been fully established yet. We describe here a case of adult onset IgAV complicated by proteinuria and pharyngitis, which was cured by no specific treatment. J. Med. Invest. 66 : 344-346, August, 2019.

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Osteolytic primary bone lymphoma in the multiple bones.

Shusuke Yagi, Robert Zheng, Seiichi Nishiyama, Yutaka Kawabata, Takayuki Ise, Kosuke Sugiura, Haruhiko Yoshinari, Toshihiko Nishisho, Yoshimi Bando, Kumiko Kagawa, Daiju Fukuda, Tomohiro Soga, Yoshihito Saijo, Kenya Kusunose, Koji Yamaguchi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Shinji Kawahito, Masashi Akaike, Masataka Sata

The journal of medical investigation : JMI   66 ( 3.4 ) 347 - 350   2019 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Primary non-Hodgkin bone lymphoma (PBL) can involve solitary or multiple destructive bone lesions such as those of the femur or pelvis humerus, and some cases have osteolytic lesions. PBL is a rare disease in adults. Thus, PBL is rarely considered a differential diagnosis of the osteolytic tumor. In addition, PBL can be underdiagnosed because patients do not experience symptoms or show objective abnormalities in the early stage. Here, we reported an elderly patient with PBL in multiple bones, including the cranial and femoral bones that were fractured due to falling. J. Med. Invest. 66 : 347-350, August, 2019.

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Lambda-like J wave due to acute myocardial infarction of the diagonal branch.

Yagi S, Ueno R, Sutou K, Wakatsuki T, Yamaguchi K, Saijo Y, Hara T, Ise T, Kusunose K, Bando M, Matsuura T, Tobiume T, Yamada H, Fukuda D, Soeki T, Akaike M, Sata M

The journal of medical investigation : JMI   66 ( 1.2 ) 185 - 187   2019 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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The culprit lesion of acute myocardial infarction could be predicted by electrocardiogram findings. However, we experienced some cases with coronary angiographic finding in the area of ST-T elevation that was different from that predicted. The lambda-like J wave could be caused by ischemia although the mechanism has not been fully elucidated. We report a case of acute myocardial infarction that showed discrepancy between ST-T elevation with lambda-like ischemic J wave in a broad area and coronary angiographical finding of diagonal branch occlusion. J. Med. Invest. 66 : 185-187, February, 2019.

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Provocation of clinically significant left ventricular outflow tract obstruction by postural change in patients with sigmoid septum.

Hirata Y, Yamada H, Kusunose K, Nishio S, Torii Y, Horike Y, Sata M

Journal of echocardiography   16 ( 4 ) 173 - 174   2018.12 [ Peer Review Accepted ]

Type of publication: Research paper (other science council materials etc.)

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Left atrial functional response after a marathon in healthy amateur volunteers.

Hirata Y, Kusunose K, Yamada H, Morita S, Torii Y, Nishio S, Zheng R, Saijo Y, Fukuda D, Yagi S, Soeki T, Sata M

The international journal of cardiovascular imaging   35 ( 4 ) 633 - 643   2018.11 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Middle-aged marathon runners have an increased risk of developing atrial fibrillation (AF). A previous study described that repetitive marathon running was associated with left atrial (LA) dysfunction. However, whether this change is common in marathon runners and which runners are at risk of LA dysfunction remain unknown. The purpose of this study was to determine which factors could predict LA dysfunction. We prospectively examined 12 healthy amateur volunteers (9 males, 31 ± 8 years old) who participated in a full marathon. All echocardiographic measurements and speckle-tracking echocardiography were performed before and after the marathon. The endpoint was defined as reduced LA reservoir strain 1 day after the marathon (non-responder group). Seven participants were in the non-responder group. Age (35 ± 9 vs. 26 ± 2 years, p = 0.020), augmentation index (76 ± 12 vs. 55 ± 8, p = 0.002), and diastolic blood pressures (83 ± 11 vs. 70 ± 7 mmHg, p = 0.021) in the non-responder group were significantly higher compared with the responder group. In multivariate linear regression analysis, only the augmentation index was an independent predictor of reduced LA reservoir function after the marathon (β = - 0.646, p = 0.023). The augmentation index was a predictive marker for reduction in LA reservoir function after a marathon in healthy amateur volunteers.

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Simultaneous Pulmonary Arterial and Venous Round Structures in Pulmonary Aspergillosis.

Yagi S, Yamazaki H, Nishio S, Kusunose K, Yamada H, Sata M

Circulation journal : official journal of the Japanese Circulation Society   83 ( 6 ) 1416 - 1416   2018.11 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Activation of Toll-Like Receptor 9 Impairs Blood Flow Recovery After Hind-Limb Ischemia.

Nishimoto S, Aini K, Fukuda D, Higashikuni Y, Tanaka K, Hirata Y, Yagi S, Kusunose K, Yamada H, Soeki T, Shimabukuro M, Sata M

Frontiers in cardiovascular medicine   5   144 - 144   2018.10 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Background: Peripheral artery disease causes significant functional disability and results in impaired quality of life. Ischemic tissue injury releases various endogenous ligands for Toll-like receptors (TLRs), suggesting the involvement of TLRs in blood flow recovery. However, the role of TLR9, which was originally known as a sensor for bacterial DNA, remains unknown. This study investigated the role of TLR9 in blood flow recovery in the ischemic limb using a mouse hind-limb ischemia model. Methods and Results: Unilateral femoral artery ligation was performed in TLR9-deficient (Tlr9 -/-) mice and wild-type mice. In wild-type mice, femoral artery ligation significantly increased mRNA expression of TLR9 in the ischemic limb (P < 0.001) and plasma levels of cell-free DNA (cfDNA) as determined by single-stranded DNA (ssDNA) (P < 0.05) and double-stranded DNA (dsDNA) (P < 0.01), which are endogenous ligands for TLR9, compared with the sham-operated group. Laser Doppler perfusion imaging demonstrated significantly improved ratio of blood flow in the ischemic to non-ischemic limb in Tlr9 -/- mice compared with wild-type mice at 2 weeks after ligation (P < 0.05). Tlr9 -/- mice showed increased capillary density and reduced macrophage infiltration in ischemic limb. Genetic deletion of TLR9 reduced the expression of TNF-α, and attenuated NF-κB activation in ischemic muscle compared with wild-type mice (P < 0.05, respectively) at 3 days after the surgery. ODN1826, a synthetic agonistic oligonucleotide for TLR9, or plasma obtained from mice with ischemic muscle promoted the expression of TNF-α in wild-type macrophages (P < 0.05), but not in Tlr9 -/- macrophages. ODN1826 also activated NF-κB signaling as determined by the degradation of IκBα in wild-type macrophages (P < 0.05), but not in Tlr9 -/- macrophages. In vitro experiments using human umbilical vein endothelial cells demonstrated that TNF-α, or conditioned medium obtained from wild-type macrophages treated with ODN1826 accelerated cell death as determined by MTS assay (P < 0.05 and P < 0.01, respectively). Conclusion: Our results suggest that ischemic muscle releases cfDNA, which activates TLR9 and enhances inflammation, leading to impairment of blood flow recovery in the ischemic limb. cfDNA-TLR9 signaling may serve as a potential therapeutic target in ischemic limb disease.

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Protease-Activated Receptor-2 Plays a Critical Role in Vascular Inflammation and Atherosclerosis in Apolipoprotein E-Deficient Mice.

Hara T, Phuong PT, Fukuda D, Yamaguchi K, Murata C, Nishimoto S, Yagi S, Kusunose K, Yamada H, Soeki T, Wakatsuki T, Imoto I, Shimabukuro M, Sata M

Circulation   138 ( 16 ) 1706 - 1719   2018.10 [ Peer Review Accepted ]

Type of publication: Research paper (other science council materials etc.)

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Protease-Activated Receptor-2 Plays a Critical Role in Vascular Inflammation and Atherosclerosis in Apolipoprotein E-Deficient Mice.

Tomoya Hara, Pham Tran Phuong, Daiju Fukuda, Koji Yamaguchi, Chie Murata, Sachiko Nishimoto, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Issei Imoto, Michio Shimabukuro, Masataka Sata

Circulation   138 ( 16 ) 1706 - 1719   2018.10 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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BACKGROUND: The coagulation system is closely linked with vascular inflammation, although the underlying mechanisms are still obscure. Recent studies show that protease-activated receptor (PAR)-2, a major receptor of activated factor X, is expressed in both vascular cells and leukocytes, suggesting that PAR-2 may contribute to the pathogenesis of inflammatory diseases. Here we investigated the role of PAR-2 in vascular inflammation and atherogenesis. METHODS: We generated apolipoprotein E-deficient ( ApoE-/-) mice lacking systemic PAR-2 expression ( PAR-2-/- ApoE-/-). ApoE-/- mice, which lack or express PAR-2 only in bone marrow (BM) cells, were also generated by BM transplantation. Atherosclerotic lesions were investigated after 20 weeks on a Western-type diet by histological analyses, quantitative reverse transcription polymerase chain reaction, and Western blotting. In vitro experiments using BM-derived macrophages were performed to confirm the proinflammatory roles of PAR-2. The association between plasma activated factor X level and the severity of coronary atherosclerosis was also examined in humans who underwent coronary intervention. RESULTS: PAR-2-/- ApoE-/- mice showed reduced atherosclerotic lesions in the aortic arch ( P<0.05) along with features of stabilized atherosclerotic plaques, such as less lipid deposition ( P<0.05), collagen loss ( P<0.01), macrophage accumulation ( P<0.05), and inflammatory molecule expression ( P<0.05) compared with ApoE-/- mice. Systemic PAR2 deletion in ApoE-/-mice significantly decreased the expression of inflammatory molecules in the aorta. The results of BM transplantation experiments demonstrated that PAR-2 in hematopoietic cells contributed to atherogenesis in ApoE-/- mice. PAR-2 deletion did not alter metabolic parameters. In vitro experiments demonstrated that activated factor X or a specific peptide agonist of PAR-2 significantly increased the expression of inflammatory molecules and lipid uptake in BM-derived macrophages from wild-type mice compared with those from PAR-2-deficient mice. Activation of nuclear factor-κB signaling was involved in PAR-2-associated vascular inflammation and macrophage activation. In humans who underwent coronary intervention, plasma activated factor X level independently correlated with the severity of coronary atherosclerosis as determined by Gensini score ( P<0.05) and plaque volume ( P<0.01). CONCLUSIONS: PAR-2 signaling activates macrophages and promotes vascular inflammation, increasing atherosclerosis in ApoE-/- mice. This signaling pathway may also participate in atherogenesis in humans.

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Right Ventricular Function and Beneficial Effects of Cardiac Rehabilitation in Patients With Systolic Chronic Heart Failure.

Kusunose K, Seno H, Yamada H, Nishio S, Torii Y, Hirata Y, Saijo Y, Ise T, Yamaguchi K, Fukuda D, Yagi S, Soeki T, Wakatsuki T, Sata M

The Canadian journal of cardiology   34 ( 10 ) 1307 - 1315   2018.10 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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BACKGROUND: It has been recognized that a comprehensive cardiac rehabilitation (CR) program improves mortality in patients with chronic heart failure. On the other hand, the magnitude of the improvement in exercise capacity after CR differs among individuals. The aim of this study was to assess the echocardiographic determinants of responders to CR using preload stress echocardiography. METHODS: We prospectively enrolled 58 chronic heart failure patients with reduced left ventricular ejection fraction (aged 62 ± 11 years; 69% male; left ventricular ejection fraction 43% ± 7%) who had received optimized medical treatment in a CR program for 5 months. We performed preload echocardiographic studies using leg positive pressure (LPP) to assess the echocardiographic parameters during preload augmentation. We defined 41 patients as a development cohort to assess the predictive value of echocardiographic variables. Next, we validated results in the remaining 17 patients as a validation cohort. RESULTS: In the development cohort, significant improvement in peak oxygen uptake (VO2) (>10%) after CR was observed in 58% patients. In a multivariable logistic regression model, the significant predictor of improvement in exercise capacity was right ventricular (RV) strain during LPP (odds ratio: 3.96 per 1 standard deviation; P = 0.01). An RV strain value of -16% during LPP had a good sensitivity of 0.79 and a specificity of 0.71 to identify patients with improvement in peak VO2. In the validation cohort, an optimal cutoff value of RV strain value was the same (area under the curve: 0.77, sensitivity: 0.78, specificity: 0.65). CONCLUSIONS: RV strain during LPP may be an echocardiographic parameter for assessing beneficial effects of CR.

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Association of Decreased Docosahexaenoic Acid Level After Statin Therapy and Low Eicosapentaenoic Acid Level with In-Stent Restenosis in Patients with Acute Coronary Syndrome

八木 秀介, D Kondo, 伊勢 孝之, 福田 大受, 山口 浩司, 若槻 哲三, 川端 豊, 伊藤 浩敬, 西條 良仁, 瀬野 弘光, 數藤 久美子, 上野 理絵, 轟 貴史, 楠瀬 賢也, 松浦 朋美, 飛梅 威, 山田 博胤, 添木 武, 島袋 充生, KI Aihara, 赤池 雅史, 佐田 政隆

Journal of Atherosclerosis and Thrombosis   26 ( 3 ) 272 - 281   2018.08 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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AIM: It is speculated that statin therapy modulates the synthesis of polyunsaturated fatty acids (PUFA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, the data available on the effects of statin therapy on the serum levels of PUFA and the subsequent impact on in-stent restenosis (ISR) in patients with acute coronary syndrome (ACS) are limited. METHODS: A total of 120 ACS patients who received emergent coronary stent implantation, follow-up coronary angiography to evaluate ISR, and new statin therapy were enrolled. We measured the serum levels of the PUFA and lipids at the onset of ACS and at the follow-up coronary angiography. RESULTS: The follow-up coronary angiography revealed 38 ISR cases. New statin therapy significantly reduced the serum levels of DHA and low-density lipoprotein cholesterol (LDL-C), while it did not affect EPA level. Single regression analysis revealed that a decreased serum level of LDL-C was associated with decreased DHA level. The multiple logistic regression analysis revealed that the decreased DHA level after statin therapy and low serum level of EPA on admission were determinants of prevalence of ISR. CONCLUSION: Statin therapy decreased the serum level of DHA with a parallel reduction in LDL-C level in patients with ACS. Decreased DHA level after statin therapy and low EPA level on admission are risk factors for ISR, indicating that in patients with ACS, decreased serum levels of DHA may be a residual target for the prevention of ISR.

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