Development of Combination Therapy Between Myocardial Regeneration and Ventricular Assist Device Support

心肌再生与心室辅助装置支持联合治疗的发展

• 批准号: 14370422
• 负责人: TAKEWA Yoshiaki
• 金额: $ 7.42万
• 依托单位: National Cardiovascular Center Research Institute
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370422/
• 关键词: Ventricular assist device; Mechanical assist circulation; Regeneration therapy; Hepatocyto growth factor; Myocardial infarction; Left ventricular remodeling; Refractory heart failure; Gene transfection; 左室リモデリング

The purpose of this study is to evaluate the usefulness of combination therapy between ventricular assist device(VAD) support and cardiac regeneration such as gene therapy or cell transplantation. I started this study when I moved from Nara Medical University to National Cardiovascular Center Research Institute.First, we examined a gene therapy for angiogenesis to acute myocardial infarction in goats under ventricular assist system(VAS). Six adult goats (56-65kg) were created the impaired heart by ligating the coronary artery and installed pulsatile bi-VADs. Hepatocyte Growth Factor(HGF) was selected as a gene of an angiogenesis factor, which also has cardioprotective activities. The HGF group (n=3) administered human HGF-cDNA plasmid of 2.0 mg in myocardium. The control group (n=3) administered beta-galactosidase plasmid similarly. Four weeks after gene transfection, all goats were tried to wean from VADs. The myocardia transfected with the hHGF-cDNA contained hHGF protein at levels a … More s high as 1.0+/-0.3 ng/g tissue 3 days after transfection. After weaning from VADs, the HGF group showed good hemodynamics while the control group showed its deterioration. The percent fractional shortening was significantly higher in the HGF group than the control group (HGF vs.control,37.9+/-1.7% vs.26.4+/-0.3%, p<0.01). LV dilatation associated with myocytes hypertorcphy and fibrotic changes were detected in the control group while not in the HGF group. Vascular density was markedly increased in the HGF group. These results suggest that gene therapy using hHGF may enhance the chance of "bridge to recovery" in the impaired heart under VAS.Second, we examined a cell transplantation to cardiomyopathy in goats supported with left VAD(LVAD). Four adult goats weighing 55.7+/-3.2 kg were created heart failure by infusing adriamycin for 5 weeks. All goats were instaled a pulsatile LVAD and maintained systmic circulation sufficiently. Two of 4 goats were infused autologus bone marrow-derived stromal cells(BMSC) which were previously cultured in vitro(BMSC group), and the rest 2 goats were not infused them (control group). All goats were continued LVAD support for 4 weeks, and cardiac function and hemodynamics were serially recorded. The BMSC group recovered better cardiac function (the LV Ejection Fraction (EF) ; from 39.3+/-2.3% to 47.0+/-14.0%) than the control group did (EF ; from 32.6+/-0.7% to 26.0+/-4.3%). Wall thinning of the myocardium was more suppressed in the BMSC group than that in the control group.In conclusion, additional regeneration therapy to severe failing heart supported with LVAD may contribute to recover cardiac function and increase the possibility of bridge to recovery. Less

这项研究的目的是评估心室辅助装置（VAD）支持和心脏再生（例如基因治疗或细胞移植）之间组合疗法的有用性。当我从奈良医科大学搬到国家心血管中心研究所时，我开始了这项研究。首先，我们检查了一种基因疗法，用于在心室辅助系统（VAS）下的山羊急性心肌梗死的血管生成。六只成年山羊（56-65公斤）是通过连接冠状动脉并安装脉冲双伏板来创建了受损心脏的。选择肝细胞生长因子（HGF）作为血管生成因子的基因，该基因也具有心脏保护活性。 HGF组（n = 3）在心肌中给予2.0 mg的人类HGF-CDNA质粒。对照组（n = 3）类似地给予β-半乳糖苷酶质粒。基因转染四个星期后，所有山羊都被试图从vads中断奶。在翻译后3天，使用HHGF-CDNA翻译的心肌在A…高达1.0 +/- 0.3 ng/g组织的含量为1.0 +/- 0.3 ng/g组织。从VADS断奶后，HGF组表现出良好的血液动力学，而对照组显示其定义。 HGF组的分数缩短百分比明显高于对照组（HGF）与Control，37.9 +/- 1.7％vs.26.4 +/- 0.3％，p <0.01）。在对照组中检测到与肌细胞高血压和纤维化变化相关的LV扩张，而在HGF组中则不在。 HGF组的血管密度显着增加。这些结果表明，使用HHGF的基因治疗可能会增加在VAS下的心脏受损中“恢复桥梁”的机会。第二，我们检查了左VAD（LVAD）支撑的山羊中的细胞移植到心肌病。通过注入阿霉素5周，产生了四只成年山羊加权55.7 +/- 3.2公斤。所有山羊均安装了脉动LVAD，并充分维护了收缩循环。 4只山羊中有2只被感染的自体骨髓衍生的基质细胞（BMSC），这些细胞先前在体外培养（BMSC组），其余的2只山羊未感染它们（对照组）。所有山羊均持续LVAD支撑4周，并记录心脏功能和血液动力学。 BMSC组恢复了更好的心脏功能（LV射血分数（EF）；从39.3 +/- 2.3％到47.0 +/- 14.0％）比对照组（EF;从32.6 +/- 0.7％到26.0 +/- 4.3％）。在BMSC组中，心肌的壁稀疏比对照组更受抑制。总而言之，对LVAD支持的严重失败心脏的额外再生治疗可能有助于恢复心脏功能并增加恢复桥梁的可能性。较少的

项目成果

Serial Pressure-Volume Analysis in Failing Heart with Pulsatile LVAD Support.

通过脉动 LVAD 支持对衰竭心脏进行串行压力-容量分析。

• 发表时间: 2004
• 期刊: ASAIO J 50(2)
• 作者: Takewa Y;Taenaka Y;Tatsumi E;Naito H;Oshikawa M;Homma A;Mizuno T;Kitamura S;Takano H
• 通讯作者: Takano H

Additional Regeneration Therapy to Severe Failing Heart Supported with VAD for Bridge to Recovery. (Abstract)

在 VAD 的支持下对严重衰竭的心脏进行额外的再生治疗，为康复提供桥梁。

• 发表时间: 2004
• 期刊: Int J Artif Organs 27(7)
• 作者: Takewa Y;Taenaka Y;Tatsumi E;Shirakawa Y;Naito H;Homma A;Mizuno T;Kitamura S;Takano H
• 通讯作者: Takano H

Assessment of ventricular function during YAD support. (Abstract)

YAD 支持期间评估心室功能。

• 发表时间: 2003
• 期刊: Int J Artif Organs 26(7)
• 作者: Takewa Y;Taenaka Y;Tatsumi E;Shirakawa Y;Naito H;Oshikawa M;Homma A;Mizuno T;Kitamura S;Takano H
• 通讯作者: Takano H

Gene Therapy for Angiogenesis under a Ventricular Assist System, Cardiovascular Regeneration Therapies Using Tissue Engineering Approaches (Mori H, Matsuda H (Eds.))

心室辅助系统下血管生成的基因治疗、使用组织工程方法的心血管再生治疗（Mori H、Matsuda H（编辑））

• 发表时间: 2004
• 作者: Takewa Y;Shirakawa Y;Taenaka Y;Tatsumi E;Sawa Y;Matsuda H;Kitamura S;Takano H
• 通讯作者: Takano H

Serial measurement of myocardial contractility during VAD. (Abstract)

VAD 期间心肌收缩力的连续测量。

• 发表时间: 2003
• 期刊: ASAIO J 49(2)
• 作者: Takewa Y;Taenaka Y;Tatsumi E;Shirakawa Y;Naito H;Oshikawa M;Homma A;Mizuno T;Kitamura S;Takano H
• 通讯作者: Takano H