The transition process, aggravating factor and therapeutic strategies from volume overload to heart failure

• Project/Area Number: 17H07135
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Applied pharmacology
• Research Institution: Toho University
• Principal Investigator: CAO Xin 東邦大学, 薬学部, 博士研究員 (40805652)
• Project Period (FY): 2017-08-25 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 容量負荷 / 拡張不全 / 慢性容量負荷 / 動静脈瘻

Outline of Final Research Achievements

The aims of this study were to evaluate the progression from creation of aorto-venocaval shunt (AVS) to diastolic heart failure (DHF), investigate the impact of chronic infusion of aldosterone on the development of DHF and find the potential therapeutic strategies. The time course of changes in cardiac function and structure were evaluated by echocardiography before surgery at 4, 12 and 24 weeks. Cardiopathy was characterized by atrial natriuretic peptide analysis, electrophysiologic and hemodynamic tests, morphometric and histological examinations at 24 weeks. AVS tended to gradually reduced ejection fraction, and impaired diatolic function acutely in 4 weeks and then kept them at a steady state until 24 weeks. Aldosterone decreased systolic function and accelerated the transition from diastolic dysfunction to systolic heart failure in the AVS rats. Amiroride suppressed inducibility of ventricular tachycardia.

Academic Significance and Societal Importance of the Research Achievements

本研究成果では、容量負荷がどのようにして生体内で拡張と収縮能に影響を与え、心不全を起こすのか、その進展過程を初めて証明した。また、アルドステロンによる圧負荷を介さない作用は心不全の収縮能に影響し、拡張障害から収縮障害への移行を促進したことを証明した。非選択制伸展活性化チャネル阻害剤は容量負荷による心室頻拍の誘発率を減少することができたことから、有効な、新しいタイプの心不全の治療薬開発の戦略構築が期待できる。

Research Products

• [Journal Article] Physiological role of nitric oxide for regulation of arterial stiffness in anesthetized rabbits. (2019)
  • Author(s): Chiba T, Sakuma K, Komatsu T, Cao X, Aimoto M, Nagasawa Y, Shimizu K, Takahashi M, Hori Y, Shirai K, Takahara A
  • Journal Title: Journal of Pharmacological Sciences Volume: 139 Issue: 1 Pages: 42-45
  • DOI: 10.1016/j.jphs.2018.11.003
  • Peer Reviewed / Open Access
• [Journal Article] Measurement of phosphodiesterase activity in the conduction system and contractile muscle of the rat heart: Evidence of regional difference (2018)
  • Author(s): Cao X, Nakamura Y, Izumi-Nakaseko H, Chiba K, Lubna NJ, Goto A, Hagiwara-Nagasawa M, Ando K, Naito AT, Takahara A, Sugiyama A
  • Journal Title: Toho Journal of Medicine Volume: 4 Pages: 103-106
  • Peer Reviewed
• [Journal Article] Selectivity of Ca2+ channel blockers for dilator actions on the isolated lower esophageal sphincter and aorta from rats (2018)
  • Author(s): Takahara A, Nozaki S, Ishiguro A, Okamura K, Cao X, Aimoto M, Nagasawa Y
  • Journal Title: Journal of Pharmacological Sciences Volume: 137 Issue: 1 Pages: 98-100
  • DOI: 10.1016/j.jphs.2018.01.012
  • Peer Reviewed / Open Access
• [Journal Article] Influence of chronic volume overload-induced atrial remodeling on electrophysiological responses to cholinergic receptor stimulation in the isolated rat atria (2018)
  • Author(s): Cao Xin、Aimoto Megumi、Fukumoto Marie、Nagasawa Yoshinobu、Tanaka Hikaru、Takahara Akira
  • Journal Title: Journal of Pharmacological Sciences Volume: 136 Issue: 2 Pages: 73-78
  • DOI: 10.1016/j.jphs.2017.12.009
  • Peer Reviewed / Open Access
• [Journal Article] Amitriptyline may have possibility to induce Brugada syndrome rather than long QT syndrome (2018)
  • Author(s): Lubna NJ, Wada T, Nakamura Y, Chiba K, Cao X, Izumi-Nakaseko H, Ando K, Naito AT, Satoh Y, Sugiyama A
  • Journal Title: Cardiovascular toxicology Volume: 18 Issue: 1 Pages: 91-98
  • DOI: 10.1007/s12012-017-9417-z
  • Peer Reviewed / Open Access
• [Journal Article] Sensitivity and reliability of halothane-anesthetized microminipigs to assess risk for drug-induced long QT syndrome (2017)
  • Author(s): Cao X, Wada T, Nakamura Y, Matsukura S, Izumi-Nakaseko H, Ando K, Naito AT, Sugiyama A
  • Journal Title: Basic & clinical pharmacology & toxicology Volume: 121 Issue: 6 Pages: 465-470
  • DOI: 10.1111/bcpt.12838
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of proarrhythmic potential of an atypical antipsychotic drug paliperidone in the halothane-anesthetized dogs (2017)
  • Author(s): Chiba K, Wada T, Nakamura Y, Cao X, Hagiwara-Nagasawa M, Izumi-Nakaseko H, Ando K, Tanaka K, Naito AT, Sugiyama A
  • Journal Title: Journal of pharmacological sciences Volume: 134 Issue: 4 Pages: 239-246
  • DOI: 10.1016/j.jphs.2017.08.002
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of Precordial Percussion Pacing Assessed in a Cardiac Standstill Microminipig Model (2017)
  • Author(s): Wada Takeshi ,Ohara Hiroshi ,Nakamura Yuji ,Cao Xin ,Izumi-Nakaseko Hiroko , Ando Kentaro , Honda Mitsuru ,Yoshihara Katsunori , Nakazato Yuji , Lurie Keith G., Sugiyama Atsushi
  • Journal Title: Circulation Journal Volume: 81 Pages: 1137-1143
  • Peer Reviewed
• [Journal Article] Assessment of pharmacological effects of Mongolian medicinal plant Adonis mongolica in guinea pigs in vivo and in vitro (2017)
  • Author(s): Izumi-Nakaseko Hiroko, Li Wei, Cao Xin, Nakamura Yuji, Ando Kentaro, Tanaka Koichiro, Enkhsaikhan Azjargal, Gotov Chojiamts , Purevjav Batkhuyag, Chultemsuren Yeruult, Nyambayar Khaliun, Dorjsuren Narantungalag, Hagiwara-Nagasawa Mihoko, Naito Atsuhiko T., Koike Kazuo, Sugiyama Astushi
  • Journal Title: Toho Journal of Medicine Volume: 3 Pages: 131-141
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Anti-atrial fibrillatory versus proarrhythmic potentials of amiodarone: a new protocol for safety evaluation in vivo (2017)
  • Author(s): Matsukura S, Nakamura Y, Cao X, Wada T, Izumi-Nakaseko H, Ando K, Sugiyama A
  • Journal Title: Cardiovascular toxicology Volume: 17 Issue: 2 Pages: 157-163
  • DOI: 10.1007/s12012-016-9369-8
  • Peer Reviewed / Open Access
• [Presentation] 持続性心房細動に対するマルチチャネル阻害薬acehytisineの有用性と安全性の分析 (2019)
  • Author(s): 曹 新, 永澤 悦伸, 川上 聡士, 相本 恵美, 高原 章
  • Organizer: 日本安全性薬理研究会 第10回学術年会
• [Presentation] 容量負荷に起因する拡張不全への進展過程の分析 (2018)
  • Author(s): 曹 新, 相本 恵美, 永澤 悦伸, 高原 章
  • Organizer: 第20回応用薬理シンポジウム
• [Presentation] Analysis of the influence of chronic volume overload on ventricle. (2018)
  • Author(s): Cao X, Nagasawa Y, Aimoto M, Zhu B, Tang Y, Takahara A
  • Organizer: 2018 International Experimental Biology and Medicine Conference
  • Int'l Joint Research
• [Presentation] Analysis of therapeutic utility of a multi-ion channel inhibitor acehytisine for paroxysmal supraventricular tachycardia in anesthetized guinea pigs. (2018)
  • Author(s): Cao X, Nagasawa Y, Aimoto M, Takahara A
  • Organizer: The 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] スニチニブは急性投与により左室収縮機能に影響を与えずに拡張機能障害を誘発する (2017)
  • Author(s): 安東賢太郎, 和田剛, 千葉浩輝, 曹新, 中村裕二, 中瀬古(泉)寛子, 内藤篤彦, 杉山篤.
  • Organizer: 第44回日本毒性学会学術年会
• [Presentation] Amitriptyline may have possibility to induce Brugada syndrome rather than long QT syndrome (2017)
  • Author(s): Lubna Nur Jaharat、Wada Takeshi、Nakamura Yuji、Chiba Koki、Cao Xin、Izumi-Nakaseko Hiroko、Ando Kentaro、Naito Atsuhiko T.、Satoh Yoshioki、Sugiyama Atsushi
  • Organizer: 第136回日本薬理学会関東部会
• [Presentation] Pharmacological effects of Mongolian medicinal plant Adonis mongolica on cardiovascular system (2017)
  • Author(s): Izumi-Nakaseko Hiroko, Li Wei, Cao Xin, Nakamura Yuji, Ando Kentaro, Tanaka Koichiro, Enkhsaikhan Azjargal, Gotov Chojiamts , Purevjav Batkhuyag, Chultemsuren Yeruult, Nyambayar Khaliun, Dorjsuren Narantungalag, Hagiwara-Nagasawa Mihoko, Naito Atsuhiko T, Koike Kazuo, Sugiyama Astushi
  • Organizer: 10th Joint Seminar on Biomedical Sciences
  • Int'l Joint Research
• [Presentation] Amitriptyline may have possibility to induce Brugada syndrome rather than long QT syndrome (2017)
  • Author(s): Lubna Nur Jaharat、Wada Takeshi、Nakamura Yuji、Chiba Koki、Cao Xin、Izumi-Nakaseko Hiroko、Ando Kentaro、Naito Atsuhiko T.、Satoh Yoshioki、Sugiyama Atsushi
  • Organizer: 10th joint Seminar on Biomedical Sciences
  • Int'l Joint Research
• [Presentation] 薬剤性QT間隔延長に対するα1アドレナリン受容体刺激薬methoxamineの影響 (2017)
  • Author(s): 川上聡士, 永澤悦伸, 神林隆一, 長澤（萩原）美帆子, 曹新, 相本恵美, 高原章
  • Organizer: 第138回日本薬理学会関東部会
• [Presentation] Aldosterone 負荷・動静脈瘻ラットにおける持続性心房細動の機序解析 -鉱質コルチコイド受容体の関与- (2017)
  • Author(s): 菊池 梨奈, 相本 恵美, 曹 新, 永澤 悦伸, 高原 章
  • Organizer: 第61回日本薬学会関東支部大会
• [Presentation] キサンチンオキシダーゼ阻害薬 febuxostat による抗心房細動作用 -aldosterone 負荷・動静脈瘻ラットを用いた検討- (2017)
  • Author(s): 栗林 あや, 相本 恵美, 曹 新, 永澤 悦伸, 高原 章
  • Organizer: 第61回日本薬学会関東支部大会
• [Presentation] Angiotensin II による血管作用の部位差に関する検討 (2017)
  • Author(s): 霜田 晃, 佐久間 清, 白取 広芸, 相本 恵美, 曹 新, 永澤 悦伸, 高原 章
  • Organizer: 第61回日本薬学会関東支部大会
• [Presentation] IKs 遮断薬が生体位心臓の再分極過程に及ぼす作用-麻酔モルモットにおける分析- (2017)
  • Author(s): 鈴木 啓太, 永澤 悦伸, 曹 新, 相本 恵美, 高原 章
  • Organizer: 第61回日本薬学会関東支部大会
• [Presentation] イソフルラン麻酔モルモットにおけるアゼラスチン及びクレマスチンの QT間隔延長作用 -テルフェナジンとの比較- (2017)
  • Author(s): 大村 賢介, 永澤 悦伸, 小林 加寿子, 曹 新, 相本 恵美, 高原 章
  • Organizer: 第136回日本薬理学会関東部会
• [Remarks] 東邦大学 教育・研究業績データベース
  • URL: https://gyoseki.toho-u.ac.jp/thuhp/KgApp?kozac=24002201&year=2018