The development of neuro-mechanical unloading therapy for myocardial infarction

• Project/Area Number: 18K15893
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: National Cardiovascular Center Research Institute (2019-2020); Kyushu University (2018)
• Principal Investigator: Saku Keita 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (40567385)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 循環器内科 / 血行動態 / 心筋梗塞 / 心力学 / 左室補助装置 / 自律神経 / 神経刺激 / 虚血性心疾患 / 心不全 / 補助循環 / 医療機器開発

Outline of Final Research Achievements

In the development of neuro-mechanical unloading therapy, we established a control algorithm to regulate both the percutaneous left ventricular assist device and the neurostimulator, after the individual verification in animal experiments. We proved that the addition of bradycardic agent to the percutaneous left ventricular assist device resulted in significant suppression of myocardial oxygen consumption, while improving hemodynamics. We also confirmed that the use of the control algorithm during the acute phase of myocardial infarction enabled stable and marked left ventricular unloading. Finally, we examined the impact of developed system in a canine model of ischemia-reperfusion, and found that the system significantly limited infarct size and worsening of heart failure.

Academic Significance and Societal Importance of the Research Achievements

心筋梗塞治療において、再還流による酸素供給再開に加えて、酸素需要を下げることは梗塞サイズが縮小するが、血行動態を保ちながら心筋酸素消費を抑制する治療法は存在しない。心筋梗塞急性期における左室補助装置と迷走神経刺激を併用した機械-神経最適減負荷アルゴリズムを構築することは、両者の機能、効果を補完することで、血行動態を悪化させることなく、著明な酸素消費低減や心筋保護効果を誘導し、最終的に梗塞サイズの極小化と遠隔期心不全の劇的な予防をもたらす可能性がある。

Research Products

• [Journal Article] Aging steepens the slope of power spectrum density of 30-minute continuous blood pressure recording in healthy human subjects (2021)
  • Author(s): Mano Jumpei、Saku Keita、Kinoshita Hiroyuki、Mannoji Hiroshi、Kanaya Shigehiko、Sunagawa Kenji
  • Journal Title: PLOS ONE Volume: 16 Issue: 3 Pages: e0248428-e0248428
  • DOI: 10.1371/journal.pone.0248428
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roxadustat Markedly Reduces Myocardial Ischemia Reperfusion Injury in Mice (2020)
  • Author(s): Deguchi H, Ikeda M, Ide T, Tadokoro T, Ikeda S, Okabe K, Ishikita A, Saku K, Matsushima S, Tsutsui H.
  • Journal Title: Circulation Journal Volume: 84 Issue: 6 Pages: 1028-1033
  • DOI: 10.1253/circj.CJ-19-1039
  • NAID: 130007846233
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2020-05-25
  • Peer Reviewed / Open Access
• [Journal Article] Prediction of haemodynamics after interatrial shunt for heart failure using the generalized circulatory equilibrium (2020)
  • Author(s): Nishikawa Takuya、Saku Keita、Uike Kiyoshi、Uemura Kazunori、Sunagawa Genya、Tohyama Takeshi、Yoshida Keimei、Kishi Takuya、Sunagawa Kenji、Tsutsui Hiroyuki
  • Journal Title: ESC Heart Failure Volume: 7 Issue: 5 Pages: 3075-3085
  • DOI: 10.1002/ehf2.12935
  • Peer Reviewed / Open Access
• [Journal Article] Prediction of hemodynamics after atrial septal defect closure using a framework of circulatory equilibrium in dogs (2020)
  • Author(s): Uike Kiyoshi
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: 319 Issue: 5 Pages: 938-947
  • DOI: 10.1152/ajpheart.00098.2020
  • Peer Reviewed / Open Access
• [Journal Article] The Partial Support of the Left Ventricular Assist Device Shifts the Systemic Cardiac Output Curve Upward in Proportion to the Effective Left Ventricular Ejection Fraction in Pressure-Volume Loop (2020)
  • Author(s): Kakino Takamori、Saku Keita、Nishikawa Takuya、Sunagawa Kenji
  • Journal Title: Frontiers in Cardiovascular Medicine Volume: 7
  • DOI: 10.3389/fcvm.2020.00163
  • Peer Reviewed / Open Access
• [Journal Article] Smart Baroreceptor Activation Therapy Strikingly Attenuates Blood Pressure Variability in Hypertensive Rats With Impaired Baroreceptor. (2020)
  • Author(s): Tohyama T, Hosokawa K, Saku K, Oga Y, Tsutsui H, Sunagawa K.
  • Journal Title: Hypertension. Volume: 75 Issue: 3 Pages: 885-892
  • DOI: 10.1161/hypertensionaha.119.13673
  • Peer Reviewed
• [Journal Article] Suppressed baroreflex peripheral arc overwhelms augmented neural arc and incapacitates baroreflex function in rats with pulmonary arterial hypertension. (2019)
  • Author(s): Shinoda M, Saku K, Oga Y, Tohyama T, Nishikawa T, Abe K, Yoshida K, Kuwabara Y, Fujii K, Ishikawa T, Kishi T, Sunagawa K, Tsutsui H.
  • Journal Title: Exp Physiol Volume: 104 Issue: 8 Pages: 1164-1178
  • DOI: 10.1113/ep087253
  • Peer Reviewed / Open Access
• [Journal Article] Mechano-chronotropic Unloading During the Acute Phase of Myocardial Infarction Markedly Reduces Infarct Size via the Suppression of Myocardial Oxygen Consumption. (2019)
  • Author(s): Sunagawa G, Saku K, Arimura T, Nishikawa T, Mannoji H, Kamada K, Abe K, Kishi T, Tsutsui H, Sunagawa K.
  • Journal Title: J Cardiovasc Transl Res. Volume: 12 Issue: 2 Pages: 124-134
  • DOI: 10.1007/s12265-018-9809-x
  • Peer Reviewed / Open Access
• [Journal Article] Estimation of the baroreflex total loop gain by the power spectral analysis of continuous arterial pressure recordings. (2019)
  • Author(s): Mannoji H, Saku K, Nishikawa T, Tohyama T, Kamada K, Abe K, Sunagawa G, Kishi T, Sunagawa K, Tsutsui H.
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: 316 Issue: 4 Pages: H828-H839
  • DOI: 10.1152/ajpheart.00681.2018
  • Peer Reviewed
• [Journal Article] Thoracic endografting increases cardiac afterload and leads to left ventricular hypertrophy in dogs. (2019)
  • Author(s): Yamashita Y, Oishi Y, Motomatsu Y, Hirayama K, Harada T, Ushijima T, Fujita S, Kimura S, Sonoda H, Tatewaki H, Tanoue Y, Sunagawa G, Nishikawa T, Saku K, Shiose A.
  • Journal Title: Eur J Cardiothorac Surg. Volume: 55 Issue: 4 Pages: 618-625
  • DOI: 10.1093/ejcts/ezy402
  • Peer Reviewed
• [Journal Article] Diabetes mellitus attenuates the pressure response against hypotensive stress by impairing the sympathetic regulation of the baroreflex afferent arc. (2019)
  • Author(s): Kamada K, Saku K, Tohyama T, Kawada T, Mannoji H, Abe K, Nishikawa T, Sunagawa G, Kishi T, Sunagawa K, Tsutsui H.
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: 316 Issue: 1 Pages: H35-H44
  • DOI: 10.1152/ajpheart.00515.2018
  • Peer Reviewed
• [Journal Article] Inhibition of TLR9-NF-kB-Mediated Sterile Inflammation Improves Pressure Overload;Induced Right Ventricular Dysfunction in Rats. (2018)
  • Author(s): Yoshida K, Abe K, Tanaka M, Saku K, Shinoda-Sakamoto M, Ishikawa T, Watanabe T, Oka M, Sunagawa K, Tsutsui H.
  • Journal Title: Cardiovasc Res. Volume: 115 Issue: 3 Pages: 658-668
  • DOI: 10.1093/cvr/cvy209
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The impact of volume loading-induced low pressure baroreflex activation on arterial baroreflex-controlled sympathetic arterial pressure regulation in normal rats (2018)
  • Author(s): Oga Yasuhiro、Saku Keita、Nishikawa Takuya、Kishi Takuya、Tobushi Tomoyuki、Hosokawa Kazuya、Tohyama Takeshi、Sakamoto Takafumi、Sunagawa Kenji、Tsutsui Hiroyuki
  • Journal Title: Physiological Reports Volume: 6 Issue: 19 Pages: e13887-e13887
  • DOI: 10.14814/phy2.13887
  • Peer Reviewed
• [Journal Article] Electrical Vagal Nerve Stimulation Ameliorates Pulmonary Vascular Remodeling and Improves Survival in Rats With Severe Pulmonary Arterial Hypertension. (2018)
  • Author(s): Yoshida K, Saku K, Kamada K, Abe K, Tanaka-Ishikawa M, Tohyama T, Nishikawa T, Kishi T, Sunagawa K, Tsutsui H.
  • Journal Title: JACC Basic Transl Sci. Volume: 12 Issue: 5 Pages: 657-671
  • DOI: 10.1016/j.jacbts.2018.07.007
  • Peer Reviewed / Open Access
• [Journal Article] Pulmonary arterial input impedance reflects the mechanical properties of pulmonary arterial remodeling in rats with pulmonary hypertension. (2018)
  • Author(s): Nishikawa T., Saku K., Kishi T., Tohyama T., Abe K, Oga Y., Arimura T., Sakamoto T., Yoshida K., Sunagawa K., Tsutsui H.
  • Journal Title: Life Sci. Volume: 21 Pages: 225-232
  • DOI: 10.1016/j.lfs.2018.10.005
  • Peer Reviewed
• [Journal Article] Derangement of open-loop static and dynamic characteristics of the carotid sinus baroreflex in streptozotocin-induced type 1 diabetic rats. (2018)
  • Author(s): Kawada T, Shimizu S, Hayama Y, Yamamoto H, Saku K, Shishido T, Sugimachi M.
  • Journal Title: Am J Physiol Regul Integr Comp Physiol. Volume: 315 Issue: 3 Pages: R553-R567
  • DOI: 10.1152/ajpregu.00092.2018
  • Peer Reviewed
• [Presentation] 循環動態視点で再考する最適な補助循環活用ストラテジー (2020)
  • Author(s): 朔 啓太
  • Organizer: 日本心不全学会総会
  • Invited
• [Presentation] Development of Smart Baroreflex Activation Therapy Targeting Blood Pressure Variability (2020)
  • Author(s): Keita Saku
  • Organizer: Hypertension Seoul
  • Int'l Joint Research / Invited
• [Presentation] PVAに着目した心筋梗塞治療 (2020)
  • Author(s): 朔 啓太
  • Organizer: 日本循環制御医学会総会
  • Invited
• [Presentation] 自律神経制御による循環器疾患治療デバイス ―病態生理からみた現状分析と課題― (2020)
  • Author(s): 朔 啓太
  • Organizer: 日本自律神経学会総会
  • Invited
• [Presentation] Upward-shift of cardiac output curve determined by the synergistic effect of support flow and left ventricular ejection fraction is the fundamental mechanism to improve hemodynamics by left ventricular assist device (2019)
  • Author(s): Keita Saku, Takamori Kakino, Kenji Sunagawa
  • Organizer: Acure meeting 2019
  • Int'l Joint Research
• [Presentation] The short-term Neuro-Mechanical Unloading therapy prior to reperfusion strikingly reduces the infarct size and prevents subsequent heart failure in a dog model of ischemia-reperfusion (2019)
  • Author(s): Keita Saku
  • Organizer: The 63rd Annual Scientific Meeting of The Korean Society of Cardiology
  • Int'l Joint Research
• [Presentation] ACSチームの底力を上げる！循環動態フレームワークで考えるImpellaの最適活用法 (2019)
  • Author(s): 朔 啓太
  • Organizer: 第42回日本心血管インターベンション治療学会東海北陸地方会
  • Invited
• [Presentation] 日本発！ニューロモデュレーションデバイスによる心不全治療への挑戦 (2019)
  • Author(s): 朔 啓太
  • Organizer: 第23回日本心不全学会学術集会
  • Invited
• [Presentation] Impella for Heart Recovery (2019)
  • Author(s): 朔 啓太
  • Organizer: 第23回日本心不全学会学術集会
  • Invited
• [Presentation] 症例から学ぶインペラによる救命/心保護ストラテジー～実臨床の役に立つ血行動態学入門～ (2019)
  • Author(s): 朔啓太
  • Organizer: 第251回日本循環器学会 関東甲信越地方会・教育セッション
• [Presentation] Impella時代の循環器診療を乗り切るための臨床血行動態学入門 (2019)
  • Author(s): 朔啓太
  • Organizer: 第48回日本心血管インターベンション治療学会北海道地方会
• [Presentation] Simulated Microgravity Exposure Strikingly Attenuates the Baroreflex Total Loop Gain and Induces Orthostatic Hypotension. (2018)
  • Author(s): Kamada K, Saku K, Mannoji H, Tohyama T, Nishikawa T, Sunagawa G, Abe K, Kishi T, Sunagawa K.
  • Organizer: 40th Annual International Conference of the IEEE Engineering in Medicine and Biology Society
  • Int'l Joint Research
• [Presentation] Reperfusion Therapy with Delayed Vagal Nerve Stimulation in Acute Myocardioal Infraction Stringly Reduces Infract Size and Improves Left Ventricular Function in The Long-term. (2018)
  • Author(s): Sunagawa G, Saku H, Arimura T, Akashi T, Kishi T, Tsutsui H, Sunagawa K.
  • Organizer: 40th Annual International Conference of the IEEE Engineering in Medicine and Biology Society
  • Int'l Joint Research
• [Presentation] The presence of baroreflex failure augments the variability of left atrial pressure and triggers acute pulmonary edema in a rat with chronic heart failure (2018)
  • Author(s): Abe K, Saku K, Mannoji H, Sunagawa G, Kamada K, Kishi T, Hoka S, Sunagawa K, Tsutsui H.
  • Organizer: European Society of Cardiology Cngress 2018
  • Int'l Joint Research
• [Presentation] Vagal nerve stimulation restores autonomic balance, super-normalizes right ventricular function and prevents the worsening of right heart failure in chronic pulmonary arterial banding model rats (2018)
  • Author(s): Yoshida K, Saku K, Sunagawa K.
  • Organizer: European Society of Cardiology Cngress 2018
  • Int'l Joint Research
• [Presentation] Unresponsiveness of baroreflex sympathetic regulation leads to orthostatic intolerance in a rat model of type 2 diabetes mellitus. (2018)
  • Author(s): Kamada K, Saku K, Tsutsui H, Sunagawa K.
  • Organizer: American Autonomic Society 2018
  • Int'l Joint Research
• [Presentation] Smart Impella unloading in the acute phase of MI markedly reduces infarct size and prevents LV dysfunction in the long term (2018)
  • Author(s): Kamada K, Saku K, Sunagawa G, Nishikawa T, Sunagawa K.
  • Organizer: The A-CURE Meeting 2018
  • Int'l Joint Research
• [Presentation] Impella combined with veno-arterial extracorporeal membrane oxygenation effectively unloads the left ventricle with improving hemodynamics in a dog model of cardiogenic shock (2018)
  • Author(s): Sunagawa G, Saku K, Nishikawa T, Akashi T, Kishi T, Tsutsui H, Sunagawa K.
  • Organizer: The A-CURE Meeting 2018
  • Int'l Joint Research
• [Presentation] Diabetes Mellitus Markedly Attenuates the Baroreflex-mediated Heart Rate Response and Makes the Histogram of Heart Rate Distribution Bimodal (2018)
  • Author(s): Kamada K, Saku K, Tohyama T, Kishi T, Nishokawa T, Mannoji H, Sunagawa G, Abe K, Sunagawa K, Tsutsui H
  • Organizer: Scientific Sessions 2018 of the American Heart Association
  • Int'l Joint Research
• [Presentation] Diabetes Mellitus Markedly Deteriorates Baroreflex Regulation of Sympathetic Nerve Activity in the Physiological Arterial Pressure Range and Exacerbates Orthostatic Intolerance. (2018)
  • Author(s): Kamada K, Saku K, Tohyama T, Kishi T, Nishokawa T, Mannoji H, Sunagawa G, Abe K, Sunagawa K, Tsutsui H.
  • Organizer: Scientific Sessions 2018 of the American Heart Association
  • Int'l Joint Research
• [Presentation] Reperfusion therapy with delayed vagal nerve stimulation in acute myocardial infarction strikingly reduces infarct size and improves left ventricular function. (2018)
  • Author(s): Sunagawa G, Saku K, Arimura T, Akashi T, Kishi T, Tsutsui H, Sunagawa K
  • Organizer: Scientific Sessions 2018 of the American Heart Association
  • Int'l Joint Research
• [Presentation] Combination of mechanical unloading (Impella) and chronotropic unloading is more powerful than mechanical unloading alone in reducing infarct size and preventing chronic heart failure (2018)
  • Author(s): Sunagawa G, Saku K, Akashi T, Kishi T, Tsutsui H, Sunagawa K.
  • Organizer: Scientific Sessions 2018 of the American Heart Association
  • Int'l Joint Research
• [Presentation] ECPELLA unloading in acute myocardial infarction reduces infarct size via powerful reduction of Left Ventricular pressure volume area. (2018)
  • Author(s): Sunagawa G, Saku K, Nishikawa T, Akashi T, KIshi T, Tsutsui H, Sunagawa K.
  • Organizer: Scientific Sessions 2018 of the American Heart Association
  • Int'l Joint Research
• [Presentation] 動脈圧反射機能不全は慢性心不全ラットにおいて著名な左房圧変動を誘発し、肺水腫リスクを増加させる (2018)
  • Author(s): 阿部潔和、朔啓太、萬納寺洋士、鎌田和宏、砂川玄哉、岸拓弥、外須美夫、砂川賢二、筒井裕之
  • Organizer: 第39回日本循環制御医学会総会
• [Presentation] 模擬微少重力は動脈圧反射の動作点ゲインを著減させることで起立不耐性を誘発する (2018)
  • Author(s): 鎌田和宏、朔啓太、萬納寺洋士、岸拓弥、遠山岳詩、西川拓也、吉田賢明、阿部潔和、砂川賢二、筒井裕之
  • Organizer: 第57回日本生体医工学会大会
• [Presentation] 循環平衡理論による心房間シャントの血行動態予測 (2018)
  • Author(s): 西川拓也、朔啓太、鵜池清、砂川玄哉、遠山岳詩、岸拓弥、上村和紀、砂川賢二、筒井裕之
  • Organizer: 第57回日本生体医工学会大会
• [Presentation] 植え込み型自律神経刺激装置による革新的肺高血圧症治療法の開 (2018)
  • Author(s): 朔啓太
  • Organizer: 第3回日本肺高血圧・肺循環学会学術集会
• [Presentation] 迷走神経刺激による革新的肺高血圧症治療法の開発 (2018)
  • Author(s): 吉田賢明、朔啓太、鎌田和宏、阿部弘太郎、石川真理子、遠山岳詩、西川拓也、岸拓弥、砂川賢二、筒井裕之
  • Organizer: 第3回日本肺高血圧・肺循環学会学術集会
• [Remarks] iVNS（経皮的迷走神経刺激）の紹介サイト
  • URL: https://ivns.circ-dynamics.jp/