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• 札幌医科大学   循環器・腎臓・代謝内分泌内科学講座  

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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

• 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.

  DOI

• 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.

  DOI

• 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

  DOI

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• 蛋白質摂取量の低下は高齢心不全患者の予後不良リスクの増加と関連するか?

  山埜光太郎, 山埜光太郎, 片野唆敏, 片野唆敏, 矢野俊之, 沼澤瞭, 長岡凌平, 本間傑, 本間傑, 藤澤佑輔, 藤澤佑輔, くぬぎ原勇人, 藤崎弘也, 大堀克彦, 大堀克彦, 神津英至, 片寄正樹, 橋本暁佳, 橋本暁佳, 古橋眞人

  日本循環器学会学術集会(Web)   88th  2024年

  J-GLOBAL

• 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(Web)   67 ( 1 )  2024年

  J-GLOBAL

• 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(Web)   67 ( 1 )  2024年

  J-GLOBAL

• 脳梗塞発症を契機に診断されたLoffler心内膜心筋炎を伴う好酸球性多発血管炎性肉芽腫症の1例—A case of eosinophilic granulomatosis with polyangiitis complicated with Loffler's endocarditis diagnosed by the onset of cerebral infarction

  大和田 渉, 矢野 俊之, 赤澤 史子, 神津 英至, 續 太郎, 宮森 大輔, 西川 諒, 永野 伸卓, 小山 雅之, 村中 敦子, 丹野 雅也

  日本内科学会雑誌   111 ( 8 ) 1580 - 1587  2022年08月

• 糖尿病合併心不全における血漿分枝鎖アミノ酸の規定因子と予後予測能の検討

  神津英至, 片野唆敏, 大堀克彦, 大堀克彦, 長岡凌平, 沼澤瞭, 小山雅之, 小山雅之, 永野伸卓, 藤戸健史, 大和田渉, 佐藤達也, 矢野俊之

  糖尿病(Web)   65 ( Suppl )  2022年

  J-GLOBAL

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• アミノ酸ー核酸代謝連関の制御による心不全の新規治療開発

  基盤研究(C)

  研究期間:

  2020年04月

  -

  2023年03月

   

  神津 英至, 久野 篤史, 矢野 俊之

  　研究概要を見る

  ラット心筋におけるプロテオミクス解析において、AMPD3と分枝鎖アミノ酸(BCAA)の代謝律速酵素である分枝鎖α-ケト酸脱水素酵素(BCKDH)が直接結合していることを同定し、BCAA代謝の制御にAMPD3が関与していることが示唆された。さらに細胞分画実験において、この結合が細胞質及び小胞体分画で見られることを同定し、心筋においてBCAAがミトコンドリア外でも代謝されている可能性を見出した。新生ラット初代心筋細胞(NRCM)において、BCKDHサブユニットのノックダウンによって脂肪滴合成能障害がみられ、BCAA代謝が脂肪酸代謝に寄与してることを同定した。2型糖尿病モデルラット(OLETF)心筋において、BCAAの蓄積及びBCKDH-AMPD3結合比の低下がみられ、糖尿病心筋におけるBCAA代謝障害にAMPD3が関与している可能性が示唆された。さらに、OLETFの心筋メタボローム解析にて、SGLT2阻害薬によって最も増加傾向を示す代謝物がBCAAを始めとするアミノ酸であることを同定し、SGLT2阻害薬の心保護効果の機序としてアミノ酸代謝修飾の関与を同定した。 また、心不全症例において、血中アミノ酸プロファイリングが既存の危険因子と独立して予後を予測することを見出した。

• 2型糖尿病による左室拡張機能障害の分子機序

  若手研究(B)

  研究期間:

  2013年04月

  -

  2015年03月

   

  神津 英至

  　研究概要を見る

  2型糖尿病において、急性圧負荷が拡張期左室伸展性を低下させる機序を解析した。2型糖尿病心ではAMP deaminaseを介したアデニンヌクレオチドの分解が亢進しており急性圧負荷中に心筋ATP濃度が低下すること、心筋ATP濃度は左室等容弛緩時定数(tau)および左室拡張末期圧と負の相関を認めること、これらの左室拡張特性は間質の線維化や細胞骨格蛋白titinの変化が出現する前より認めることを明らかにした。