論文 - 神津　英至

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Is an Independent Risk Factor for the Development of Ischemic Heart Disease ― A 10-Year Cohort Study ―

Toshifumi Ogawa, Tatsuya Sato, Marenao Tanaka, Yukinori Akiyama, Kei Nakata, Hidemichi Kouzu, Kazuma Mori, Hiroki Aida, Wataru Kawaharata, Itaru Hosaka, Toru Suzuki, Nagisa Hanawa, Masato Furuhashi

Circulation Reports ( Japanese Circulation Society )   2025年04月

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Prognostic implication of sarcopenia diagnosed by updated Asian Working Group for Sarcopenia criteria in older patients with heart failure: Utility and limitation

Satoshi Katano, Kotaro Yamano, Toshiyuki Yano, Ryo Numazawa, Ryohei Nagaoka, Suguru Honma, Yusuke Fujisawa, Yasuhiro Miki, Yuhei Takamura, Hayato Kunihara, Hiroya Fujisaki, Hidemichi Kouzu, Katsuhiko Ohori, Masaki Katayose, Akiyoshi Hashimoto, Masato Furuhashi

The Journal of nutrition, health and aging ( Elsevier BV )  29 ( 1 ) 100434 - 100434  2025年01月

DOI

セマグルチド注射薬により20年間のインスリン強化療法から離脱できた2型糖尿病の1例

寺沢 誠, 中田 圭, 大久保 武志, 小川 俊史, 隅田 健太郎, 佐藤 達也, 神津 英至, 矢野 俊之, 古橋 眞人

糖尿病 ( (一社)日本糖尿病学会 )  67 ( 12 ) 511 - 511  2024年12月

腹腔鏡下胃スリーブ状切除術によりインスリン抵抗性-インスリン必要量増加-体重増加の悪循環を脱し、肥満関連合併症の改善が得られた1例

小川 俊史, 佐藤 達也, 大久保 武志, 寺沢 誠, 中田 圭, 隅田 健太郎, 神津 英至, 矢野 俊之, 矢島 諒人, 伊東 竜哉, 竹政 伊知朗, 古橋 眞人

日本内分泌学会雑誌 ( (一社)日本内分泌学会 )  100 ( 4 ) 805 - 805  2024年12月

Contribution of MLKL to the development of doxorubicin-induced cardiomyopathy and its amelioration by rapamycin.

Masaki Shimizu, Wataru Ohwada, Toshiyuki Yano, Hidemichi Kouzu, Tatsuya Sato, Toshifumi Ogawa, Arata Osanami, Yuki Toda, Hiroshi Nagahama, Masaya Tanno, Tetsuji Miura, Atsushi Kuno, Masato Furuhashi

Journal of pharmacological sciences   156 ( 1 ) 9 - 18  2024年09月  [国内誌]

　概要を見る

Necroptosis, necrosis characterized by RIPK3-MLKL activation, has been proposed as a mechanism of doxorubicin (DOX)-induced cardiomyopathy. We showed that rapamycin, an mTORC1 inhibitor, attenuates cardiomyocyte necroptosis. Here we examined role of MLKL in DOX-induced myocardial damage and protective effects of rapamycin. Cardiomyopathy was induced in mice by intraperitoneal injections of DOX (10 mg/kg, every other day) and followed for 7 days. DOX-treated mice showed a significant decline in LVEF assessed by cardiac MRI (45.5 ± 5.1% vs. 65.4 ± 4.2%), reduction in overall survival rates, and increases in myocardial RIPK3 and MLKL expression compared with those in vehicle-treated mice, and those changes were prevented by administration of rapamycin (0.25 mg/kg) before DOX injection. In immunohistochemical analyses, p-MLKL signals were detected in the cardiomyocytes of DOX-treated mice, and the signals were reduced by rapamycin. Mlkl+/- and Mlkl-/- mice were similarly resistant to DOX-induced cardiac dysfunction, indicating that a modest reduction in MLKL level is sufficient to prevent the development of DOX-induced cardiomyopathy. However, evidence of cardiomyocyte necrosis assessed by C9 immunostaining, presence of replacement fibrosis, and electron microscopic analyses was negligible in the myocardium of DOX-treated mice. Thus, MLKL-mediated signaling contributes to DOX-induced cardiac dysfunction primarily by a necrosis-independent mechanism, which is inhibitable by rapamycin.

DOI PubMed

Adverse plasma branched‐chain amino acid profile mirrors fatty muscle degeneration in diabetic heart failure patients

Hidemichi Kouzu, Toshiyuki Yano, Satoshi Katano, Wataru Kawaharata, Keishi Ogura, Ryo Numazawa, Ryohei Nagaoka, Katsuhiko Ohori, Ryo Nishikawa, Wataru Ohwada, Takefumi Fujito, Nobutaka Nagano, Masato Furuhashi

ESC Heart Failure ( Wiley )   2024年05月

　概要を見る

Abstract Aims Elevated plasma branched‐chain amino acids (BCAAs) are tightly linked to incident diabetes and its complications, while lower BCAAs are associated with adverse outcomes in the elderly and heart failure (HF) patients. The interplay between body compositions and plasma BCAAs, especially under the influence of co‐morbid diabetes in HF patients, is not well understood. Here, we examined the impact of diabetes on the prognostic value of plasma BCAA and its association with body compositions in HF patients. Methods and results We retrospectively examined 301 HF patients (70 ± 15 years old; 59% male), among which 36% had diabetes. Blood samples for plasma BCAA measurements were collected in a fasting state after stabilization of HF and analysed using ultraperformance liquid chromatography. A dual‐energy X‐ray absorptiometry scan assessed regional body compositions, and muscle wasting was defined as appendicular skeletal muscle mass index (ASMI) < 7.00 and <5.40 kg/m² for males and females, respectively, according to the criteria of the Asian Working Group for Sarcopenia. Although analyses of covariance revealed that plasma BCAAs were significantly higher in diabetic patients, low valine (<222.1 nmol/mL) similarly predicted adverse events defined by HF hospitalization, lethal arrhythmia, or all‐cause death in both diabetic and non‐diabetic patients independently of age, sex, and NT‐proBNP (adjusted hazard ratio [HR] 3.1, 95% confidence interval [CI] of 1.1–8.6 and adjusted HR 2.67, 95% CI 1.1–6.5, respectively; P for interaction 0.88). In multivariate linear regression analyses comprising age, sex, and regional body compositions as explanatory variables, plasma BCAAs were positively correlated with visceral adipose tissue area in non‐diabetic patients (standardized β coefficients [β] = 0.44, P < 0.001). In contrast, in diabetic patients, plasma BCAAs were correlated positively with ASMI (β = 0.49, P = 0.001) and negatively with appendicular fat mass index (AFMI; β = −0.42, P = 0.004). Co‐morbid diabetes was independently associated with muscle wasting (adjusted odds ratio 2.1, 95% CI 1.1–4.0) and significantly higher plasma 3‐methylhistidine level, a marker of myofibrillar degradation. In diabetic patients, ASMI uniquely showed a J‐shaped relationship with AFMI, and in a subgroup of HF patients with muscle wasting, diabetic patients showed 12% higher AFMI than non‐diabetic patients despite comparable ASMI reductions. Conclusions Despite higher plasma BCAA levels in HF patients with diabetes, the prognostic value of low valine remained consistent regardless of diabetes status. However, low BCAAs were distinctly associated with fatty muscle degeneration in the extremities in diabetic patients, suggesting the importance of targeted interventions to prevent such tissue remodelling in this population.

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Associations between in‐hospital daily protein intake and adverse clinical outcomes in older patients with heart failure

Satoshi Katano, Toshiyuki Yano, Kotaro Yamano, Ryo Numazawa, Ryohei Nagaoka, Suguru Honma, Yusuke Fujisawa, Katsuhiko Ohori, Hidemichi Kouzu, Hayato Kunihara, Hiroya Fujisaki, Masaki Katayose, Akiyoshi Hashimoto, Masato Furuhashi

ESC Heart Failure ( Wiley )   2024年05月

　概要を見る

Abstract Aims The adverse effects of low daily protein intake (DPI) on clinical outcomes in patients with heart failure (HF) are known; however, an optimal DPI to predict event adverse outcomes remains undetermined. Moreover, whether protein restriction therapy for chronic kidney disease is applicable in patients with HF and renal dysfunction remains unclear. Methods and results In this single‐centre, ambispective cohort study, we included 405 patients with HF aged ≥65 years (mean age, 78.6 ± 7.5 years; 50% women). DPI was estimated from consumption over three consecutive days before discharge and normalized relative to the ideal body weight [IBW, 22 kg/m² × height (m)²]. The primary outcome was a composite of all‐cause mortality and HF‐related readmission within the 2 year post‐discharge period. Results During an average follow‐up period of 1.49 ± 0.74 years, 100 patients experienced composite events. Kaplan–Meier survival curves revealed a significantly lower composite event‐free rate in patients within the lowest quartile of DPI than in the upper quartiles (log‐rank test, P = 0.02). A multivariate Cox proportional hazards analysis after adjusting for established prognostic markers and non‐proteogenic energy intake revealed that patients in the lowest DPI quartile faced a two‐fold higher risk of composite events than those in the highest quartile [hazard ratio (HR), 2.03; 95% confidence interval (CI), 1.08–3.82; P = 0.03]. The composite event risk linearly increased as DPI decreased (P for nonlinearity = 0.90), with each standard deviation (0.26 g/kg IBW/day) decrease in DPI associated with a 32% increase in composite event risk (HR, 1.32; 95% CI, 1.10–1.71; P = 0.04). There was significant heterogeneity in the effect of DPI, with the possible disadvantage of lower DPI in patients with HF with cystatin C‐based estimated glomerular filtration rate <30 mL/min/1.73 m². The cutoff value of DPI for predicting the occurrence of composite events calculated from the Youden index was 1.12 g/kg IBW/day. Incorporating a DPI < 1.12 g/kg IBW/day into the baseline model significantly improved the prediction of post‐discharge composite events (continuous net reclassification improvement, 0.294; 95% CI, 0.072–0.516; P = 0.01). Conclusions Lower DPI during hospitalization is associated with an increased risk of mortality and HF readmission independent of non‐proteogenic energy intake, and the possible optimal DPI for predicting adverse clinical outcomes is >1.12 g/kg IBW/day in older patients with HF. Caution is warranted when protein restriction therapy is administered to older patients with HF and renal dysfunction.

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Which came first: Sarcopenia or weight loss?

Katsuhiko Ohori, Toshiyuki Yano, Satoshi Katano, Ryohei Nagaoka, Ryo Numazawa, Kotaro Yamano, Yusuke Fujisawa, Hidemichi Kouzu, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Wataru Ohwada, Masato Furuhashi

Geriatrics &amp; Gerontology International ( Wiley )   2024年04月

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Downregulation of Mitochondrial Fusion Protein Expression Affords Protection from Canonical Necroptosis in H9c2 Cardiomyoblasts

Yuki Toda, Sang-Bing Ong, Toshiyuki Yano, Atsushi Kuno, Hidemichi Kouzu, Tatsuya Sato, Wataru Ohwada, Yuki Tatekoshi, Toshifumi Ogawa, Masaki Shimizu, Masaya Tanno, Masato Furuhashi

International Journal of Molecular Sciences ( MDPI AG )  25 ( 5 ) 2905 - 2905  2024年03月

　概要を見る

Necroptosis, a form of necrosis, and alterations in mitochondrial dynamics, a coordinated process of mitochondrial fission and fusion, have been implicated in the pathogenesis of cardiovascular diseases. This study aimed to determine the role of mitochondrial morphology in canonical necroptosis induced by a combination of TNFα and zVAD (TNF/zVAD) in H9c2 cells, rat cardiomyoblasts. Time-course analyses of mitochondrial morphology showed that mitochondria were initially shortened after the addition of TNF/zVAD and then their length was restored, and the proportion of cells with elongated mitochondria at 12 h was larger in TNF/zVAD-treated cells than in non-treated cells (16.3 ± 0.9% vs. 8.0 ± 1.2%). The knockdown of dynamin-related protein 1 (Drp1) and fission 1, fission promoters, and treatment with Mdivi-1, a Drp-1 inhibitor, had no effect on TNF/zVAD-induced necroptosis. In contrast, TNF/zVAD-induced necroptosis was attenuated by the knockdown of mitofusin 1/2 (Mfn1/2) and optic atrophy-1 (Opa1), proteins that are indispensable for mitochondrial fusion, and the attenuation of necroptosis was not canceled by treatment with Mdivi-1. The expression of TGFβ-activated kinase (TAK1), a negative regulator of RIP1 activity, was upregulated and the TNF/zVAD-induced RIP1-Ser166 phosphorylation, an index of RIP1 activity, was mitigated by the knockdown of Mfn1/2 or Opa1. Pharmacological TAK1 inhibition attenuated the protection afforded by Mfn1/2 and Opa1 knockdown. In conclusion, the inhibition of mitochondrial fusion increases TAK1 expression, leading to the attenuation of canonical necroptosis through the suppression of RIP1 activity.

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Impact of Mitochondrial Dynamics on Necroptosis in Cardiomyocytes(タイトル和訳中)

戸田 悠貴, 矢野 俊之, 久野 篤史, 丹野 雅也, 神津 英至, 佐藤 達也, 大和田 渉, 舘越 勇輝, 小川 俊史, 清水 将輝, 古橋 眞人

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  88回   PJ080 - 3  2024年03月

心筋細胞のネクロプトーシスにおけるミトコンドリア動態の影響(Impact of Mitochondrial Dynamics on Necroptosis in Cardiomyocytes)

戸田 悠貴, 矢野 俊之, 久野 篤史, 丹野 雅也, 神津 英至, 佐藤 達也, 大和田 渉, 舘越 勇輝, 小川 俊史, 清水 将輝, 古橋 眞人

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  88回   PJ080 - 3  2024年03月

Contribution of MLKL to the Development of Doxorubicin-induced Cardiomyopathy(タイトル和訳中)

清水 将輝, 大和田 渉, 矢野 俊之, 神津 英至, 佐藤 達也, 長南 新太, 小川 俊史, 戸田 悠貴, 久野 篤史, 丹野 雅也, 古橋 眞人

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  88回   PJ073 - 1  2024年03月

ドキソルビシン誘発性心筋症の発症におけるMLKLの寄与(Contribution of MLKL to the Development of Doxorubicin-induced Cardiomyopathy)

清水 将輝, 大和田 渉, 矢野 俊之, 神津 英至, 佐藤 達也, 長南 新太, 小川 俊史, 戸田 悠貴, 久野 篤史, 丹野 雅也, 古橋 眞人

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  88回   PJ073 - 1  2024年03月

Role of AMP deaminase in diabetic cardiomyopathy

Tetsuji Miura, Hidemichi Kouzu, Masaya Tanno, Yuki Tatekoshi, Atsushi Kuno

Molecular and Cellular Biochemistry ( Springer Science and Business Media LLC )   2024年02月

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中枢性尿崩症合併糖尿病患者に対するSGLT2阻害薬+経口GLP1製剤による治療の1例

中田 圭, 佐藤 達也, 小川 俊史, 大和田 渉, 隅田 健太郎, 神津 英至, 矢野 俊之, 古橋 眞人

糖尿病 ( (一社)日本糖尿病学会 )  67 ( 1 ) 40 - 40  2024年01月

チルゼパチドが著効した後腹膜滑膜肉腫合併の若年肥満2型糖尿病の症例

大久保 武志, 佐藤 達也, 小川 俊史, 中田 圭, 大和田 渉, 隅田 健太郎, 神津 英至, 矢野 俊之, 古橋 眞人

糖尿病 ( (一社)日本糖尿病学会 )  67 ( 1 ) 38 - 38  2024年01月

チルゼパチドが著効した後腹膜滑膜肉腫合併の若年肥満2型糖尿病の症例

大久保 武志, 佐藤 達也, 小川 俊史, 中田 圭, 大和田 渉, 隅田 健太郎, 神津 英至, 矢野 俊之, 古橋 眞人

糖尿病 ( (一社)日本糖尿病学会 )  67 ( 1 ) 38 - 38  2024年01月

中枢性尿崩症合併糖尿病患者に対するSGLT2阻害薬+経口GLP1製剤による治療の1例

中田 圭, 佐藤 達也, 小川 俊史, 大和田 渉, 隅田 健太郎, 神津 英至, 矢野 俊之, 古橋 眞人

糖尿病 ( (一社)日本糖尿病学会 )  67 ( 1 ) 40 - 40  2024年01月

Relationship between serum iron level and physical function in heart failure patients is lost by presence of diabetes.

Katsuhiko Ohori, Toshiyuki Yano, Satoshi Katano, Ryohei Nagaoka, Ryo Numazawa, Kotaro Yamano, Yusuke Fujisawa, Hidemichi Kouzu, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Wataru Ohwada, Tatsuya Sato, Masato Furuhashi

ESC heart failure    2023年12月  [国際誌]

　概要を見る

AIMS: Iron deficiency (ID) is common in patients with heart failure (HF) and is reportedly associated with exercise intolerance and impaired quality of life. Iron supplementation therapy in HF patients with ID improves exercise capacity. Conversely, protective roles of iron depletion in the development of diabetes mellitus (DM) and its complications have been proposed. This study aimed to determine the impact of ID on physical function in HF patients with and without DM. METHODS AND RESULTS: We enrolled consecutive patients who were admitted to our institute for HF diagnosis and management. The short physical performance battery (SPPB) was used to evaluate physical function, and low physical function was defined as an SPPB score of <10 points as individuals with SPPB scores of <10 points are most likely to be classified as frail and are at high risk for disability and future adverse events, including death. ID was defined as serum ferritin < 100 or 100-299 ng/mL when transferrin saturation (TSAT) was <20% according to the HF guidelines. Among the 562 HF patients (72 ± 14 years old; 56% male), 329 patients (58%) and 191 patients (34%) had ID and low physical function, respectively. Multivariate logistic regression analysis showed that TSAT as a continuous variable, but not ID, was a predictor of low physical function (odds ratio: 0.980, P = 0.024). Subgroup analysis showed that a significant association between low TSAT and low physical function was lost in HF patients with DM (P for interaction < 0.001). A spline dose-response curve for the relationship between TSAT and risk of low physical function with adjustments for covariates associated with low physical function in non-DM patients was almost linear with an increase in the risk of low physical function as the TSAT increased, but such a relationship was not found in the analyses of DM patients. A lack of close TSAT-SPPB relationship in HF patients with DM was confirmed also in a propensity-score-matched cohort. CONCLUSIONS: TSAT as a continuous variable, but not ID, was independently associated with physical function in HF patients, and a significant association was lost in patients with HF and DM, suggesting a limited impact of iron supplementation therapy in HF patients with DM.

DOI PubMed

Coexistence of sarcopenia and self‐reported weight loss is a powerful predictor of mortality in older patients with heart failure

Katsuhiko Ohori, Toshiyuki Yano, Satoshi Katano, Ryohei Nagaoka, Ryo Numazawa, Kotaro Yamano, Yusuke Fujisawa, Hidemichi Kouzu, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Wataru Ohwada, Masato Furuhashi

Geriatrics &amp; Gerontology International ( Wiley )   2023年12月

　概要を見る

Aim We examined whether the addition of self‐reported weight loss improves the accuracy of prediction of mortality caused by sarcopenia in heart failure (HF) patients. Methods We enrolled 477 HF patients (mean age 77 years) who received combined assessment of sarcopenia and self‐reported weight loss. Sarcopenia was diagnosed according to the criteria of the Asian Working Group for Sarcopenia. If the patients answered “yes” to the question “have you lost 2 kg or more in the past 6 months?”, they were diagnosed as having self‐reported weight loss. Results Sarcopenia and self‐reported weight loss coexisted in 32% of patients. During a median follow‐up period of 763 days, 65 patients (15%) died. Kaplan–Meier curves showed a significantly higher rate of mortality in HF patients with both sarcopenia and self‐reported weight loss than in HF patients with sarcopenia alone. Multivariate Cox proportional hazards analysis showed that the coexistence of sarcopenia and self‐reported weight loss is an independent predictor of mortality in HF patients. Inclusion of the coexistence of sarcopenia and self‐reported weight loss in the baseline model consisting of established prognostic markers significantly improved both the net reclassification index and the integrated discrimination index. Conclusions The coexistence of sarcopenia and self‐reported weight loss is a powerful predictor of mortality in HF patients. Geriatr Gerontol Int 2023; ••: ••–••.

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