心臓周囲への脂肪組織移植による冠動脈疾患に対する新規治療法の開発

2011 Fiscal Year Annual Research Report

• Project/Area Number: 23659420
• Research Institution: The University of Tokushima
• Principal Investigator: 佐田 政隆 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 教授 (80345214)
• Co-Investigator(Kenkyū-buntansha): 添木 武 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 講師 (60393211) ; 竹谷 善雄 徳島大学, 病院, 助教 (50563615) ; 山口 浩司 徳島大学, 病院, 助教 (90531377)
• Project Period (FY): 2011-04-28 – 2012-03-31
• Keywords: 動脈硬化 / 脂肪 / 移植 / 炎症 / 外膜 / 血管新生

Research Abstract

冠動脈疾患患者の冠動脈周囲に豊富に存在する炎症性脂肪組織を炎症の少なし皮下脂肪組織によって置換することによって動脈硬化を治療するという革新的血管保護療法の開発を目的とした。その戦略の科学的裏づけをするために、まず、冠動脈疾患をおこしてしまった患者における心臓周囲脂肪組織の性状を明らかにした。
ヒト冠動脈周囲脂肪組織を採取すると、冠動脈疾患者(CAD群)では非冠動脈疾患患者(Non-CAD群)に比して、IL-1β・IL-6・TNFαなどのサイトカインの発現が有意に増強していた。CD68陽性マクロファージは、CAD群のEATにおいて有意に増加していた。また、TLRS,MyD88,NLRP3といった病原体センサーの発現が亢進していた。M1マクロファージとM2マクロファージの相対比はCAD群のEATにおいて増加しており、冠動脈病変の重症度スコアと有意な正の相関が認められた。冠動脈病変のある患者のEATにおいては、マクロファージの浸潤増加しており、その極性が相対的に炎症側にシフトしており、冠動脈疾患の病態に関与していることが明らかとなった。興味深いことには、冠動脈疾患患者においても、内胸動脈周囲脂肪組織では、皮下脂肪と同様に炎症性の変化が亢進していなかった。心臓周囲脂肪組織における慢性炎症が、冠動脈疾患の病態に関与していること、周囲脂肪組織の性状によって内胸動脈が動脈硬化惹起性ストレスから保護されていることが示唆された。
次にマウス大腿動脈のワイヤー傷害モデルにおいて、周囲脂肪組織が病原形成に及ぼす影響を検はした。痩せたマウスの皮下脂肪移植では病変形成が抑制され、肥満マウスの内臟脂肪移植では病変形成が促進することがわかった。
以上の基礎的な裏付けをもとに、脂肪移植に新規治療法を技術開発をするため、ブタのモデルを用いて脂肪移植技術を併用するバイパス技術の開発を開始した。

Research Products

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• [Journal Article] Augmented angiogenesis in adventitia promotes growth of atherosclerotic plaque in apolipoprotein E-deficient mice (2011)
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• [Journal Article] Bosentan improves systemic sclerosis-related peripheral circulation insufficiency (2011)
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• [Journal Article] Synergistic protection against vascular inflammation with a calcium channel blocker and a statin (2011)
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• [Journal Article] Removal of pinched-off central venous catheter (2011)
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• [Journal Article] Enhanced inflammation in epicardial fat in patients with coronary artery disease (2011)
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• [Journal Article] Ventricular tachycardia in cardiac sarcoidosis controlled by radiofrequency catheter ablation (2011)
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• [Journal Article] Pre-clinical data on the role of mineralocorticoid receptor antagonists in reversing vascular inflammation (2011)
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• [Journal Article] Preparation of double-raschel knitted silk vascular grafts and evaluation of short-term function in a rat abdominal aorta (2011)
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• [Journal Article] A synthetic prostacycline agonist, ONO-1301, ameliorates ventricular remodeling after acute myocardial infarction via up-regulation of HGF in rat (2011)
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• [Journal Article] Elevated concentrations of pentraxin 3 are associated with coronary plaque vulnerability (2011)
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• [Journal Article] High phosphate diet reduces atherosclerosis formation in apolipoprotein E-deficient mice (2011)
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• [Journal Article] Local persistent hypercoagulability after sirolimus-eluting stent implantation in patients with stable angina (2011)
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• [Journal Article] Ezetimibe monotherapy ameliorates vascular function in patients with hypercholesterolemia through decreasing oxidative stress (2011)
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• [Journal Article] Validation of longitudunal peak systolic strain by speckle tracking echocaraiography with visual assessment and myocardial perfusion SPECT in patients with regional asynergy (2011)
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• [Journal Article] Plasma heparin cofactor II activity is inversely associated with left atrial volume and diastolic dys function in humans with cardiovascular risk factors (2011)
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• [Journal Article] Acute hemodynamic effects of adaptive servo ventilation in patients withpulmorary hypertension (2011)
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• [Journal Article] Activation of peroxisome proliferator-activated reoeptor α in megakaryocytes reduces platelet-derived growth factor-BB in platelets (2011)
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• [Journal Article] Serial imaging changes during treatment of Takayasu arteriyis with pulmonary artery stenosis (2011)
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• [Journal Article] Chronic inflammation and atherosclerosis : A critical role for renin angiotensin system that is a ctivated by life-style related diseases (2011)
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• [Journal Article] Effect of low-dose(1 mg/day) pitavastatin on left ventricular diastolic function and albuminuri a in patients with hyperlipidemia (2011)
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• [Journal Article] Observation of stort-term atervastain-induced clanges in ocronary arterial plaque propeties using integrated backscatter intravascular ultrasound in a patient (2011)
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• [Journal Article] Relationships among hyperuricemia, metabolic syndrome, and endothelial function (2011)
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• [Journal Article] Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue (2011)
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• [Journal Article] Comparison of chronic-stage histopathological findings among 3 coronarystents implanted in the same patient (2011)
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• [Journal Article] A patient who developed toe neacsis due to poor blood circulation afteran interdigital tick bite (2011)
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• [Journal Article] Reproducibility and diagnostic accuracy of three-layer speckle tracking echocardiography in a swine chromic ischemia model (2011)
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• [Journal Article] Aliskiren in combination with valsartan exerts synergistic protective effects against ventricular remodeling after myocardial infarction in mice (2011)
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• [Journal Article] A synthetic prostacyclin agonist thrombozane synthase inbibitory activity, ONO-1301, proteces myocardium from ischemia/reperfusion injury (2011)
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• [Journal Article] The ATP-binding cassette transporter ABCG2 protects against pressure overload-induced cardiac hypertrophy and heart failure by promoting angiogenesis and antioxidart response (2011)
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• [Journal Article] Intensive glucose lowering in cardiovascular risk management (2011)
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• [Presentation] Detection of Cardiac Involvement in Patients with Sarcoidosis Using Cardiac Magnetic Resonance (2011)
  • Author(s): Iwase, T, et al
  • Organizer: AHA Scientific Sessions 2011
  • Place of Presentation: Orange Country Conversion Center, Orlando, Florida
  • Year and Date: 20111112-20111116
• [Presentation] Effects of Telmisartan on Inflammator Cytokines and Coronary Plaque Component Assessed by Integrated Backscatter Intravascular Ultrasound in Hypertensive Patients (2011)
  • Author(s): Yamaguchi, K, et al
  • Organizer: AHA Scientific Sessions 2011
  • Place of Presentation: Orange Country Conversion Center, Orlando, Florida
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• [Presentation] Ultrasonic Tissue Characterization of Carotid Artery Plaque using High-resolution Integrated Backscatter Imaging, Validation Study with Histological Corrmelation (2011)
  • Author(s): Bando, M, et al
  • Organizer: AHA Scientific Sessions 2011
  • Place of Presentation: Orange Countr Conversion Center, Orlando, Florida
  • Year and Date: 20111112-20111116
• [Presentation] Pentraxin 3 is a Local Inflammatory Maker in Atrial Fibrillation (2011)
  • Author(s): Soeki, T, et al
  • Organizer: AHA Scientific Sessions 2011
  • Place of Presentation: Orange Country Conversion Center, Orlando, Florida Orlando
  • Year and Date: 20111112-20111116
• [Presentation] HMGB1 Sigral via TLR9 Plays Critical Role in Vascular Remodeling (2011)
  • Author(s): Higashida, M, et al
  • Organizer: AHA Scientific Sessions 2011
  • Place of Presentation: Orange Country Conversion Center, Orlando, Florida
  • Year and Date: 20111112-20111116
• [Presentation] Single-Beat Assessment of Left Ventricular Systolic and Diastolic Function during Atrial Fibrillaion using Myocardial Strain and Strain Rate (2011)
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  • Organizer: AHA Scientific Sessions 2011
  • Place of Presentation: Orange Country Conversion Center, Orlando, Florida
  • Year and Date: 20111112-20111116
• [Presentation] 心臓周囲脂肪におけるインフラマゾームの病態的意義 (2011)
  • Author(s): 佐藤寛美, 他
  • Organizer: 第32回日本肥滿学会
  • Place of Presentation: 淡路夢舞台国際会議場(兵庫県)
  • Year and Date: 20110923-20110924
• [Presentation] テルミサルタンは、beyond AT1R作用により動脈硬化抑制作用を示す (2011)
  • Author(s): 塩田あすか, 他
  • Organizer: 第32回日本肥滿学会
  • Place of Presentation: 淡路夢舞台国際会議場(兵庫県)
  • Year and Date: 20110923-20110924
• [Presentation] エイコサペンタエン酸は高脂血症において脂肪酸構成を変化させ、血管内皮機能を改善する (2011)
  • Author(s): 山川研, 他
  • Organizer: 第32回日本肥滿学会
  • Place of Presentation: 淡路夢舞台国際会議場(兵庫県)
  • Year and Date: 20110923-20110924
• [Presentation] Heparin Cofactor II Promotes Angiogenesis via an AMPK-eNOS Signaling Pathway (2011)
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  • Organizer: American Heart Association HBPR 2011
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  • Year and Date: 20110920-20110924
• [Presentation] Impact of abdominal obesity and insulin resistance on cardiovascular events in Japanese obesity-endemic area : Okinawa Tomishiro Cohort Study (2011)
  • Author(s): Shimabukuro, M, et al
  • Organizer: ESC Congress 2011
  • Place of Presentation: Paris Nord Villepinte exhibition center, Paris
  • Year and Date: 20110827-20110831
• [Presentation] Long-term local inflammatory and coagulative responses after coronary artery stenting with drug-eluting stent (2011)
  • Author(s): Wakatsuki, T, et al
  • Organizer: ESC Congress 2011
  • Place of Presentation: Paris Nod Villepinte exhibition center Paris
  • Year and Date: 20110827-20110831
• [Presentation] Elevated concentration of pentraxin 3 is associated with local inflammation in atrial fibrilation (2011)
  • Author(s): Soeki, T, et al
  • Organizer: ESC Congress 2011
  • Place of Presentation: Paris Nord Villepinte exhibition center, Paris
  • Year and Date: 20110827-20110831
• [Presentation] Deteriorationof right ventricular myocardial systolic function in monocrotaline-induced pulmonary arterial hypertension canine model : echocardiographic evaluation by 2D speckle tracking (2011)
  • Author(s): Nishio, S, et al
  • Organizer: ESC Congrss 2011
  • Place of Presentation: Paris Nord Villepinte exhibition center, Paris
  • Year and Date: 20110827-20110831
• [Presentation] GLP-1 receptor agonist attenuates vascular remodeling after endovascular injury (2011)
  • Author(s): Hirata, Y, et al
  • Organizer: ESC Congress 2011
  • Place of Presentation: Paris Nord Villepinte exhibition center, Paris Paris
  • Year and Date: 20110827-20110831
• [Presentation] HMGB1/ILR9 pathway plays a critical role in chronic inflammation and vascular remodeling after endovascular injury (2011)
  • Author(s): Higashida, M, et al
  • Organizer: ESC Congress 2011
  • Place of Presentation: Paris Nord Villepinte exhibition center, Paris aris
  • Year and Date: 20110827-20110831