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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

基本信息

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

项目摘要

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

本研究的目的是评价心室辅助装置（VAD）支持与心脏再生（如基因治疗或细胞移植）之间的联合治疗的有效性。我从奈良医科大学转到国立心血管中心研究所时开始了这项研究。首先，我们在心室辅助系统（VAS）下检查了山羊急性心肌梗死血管新生的基因治疗。6只成年山羊（56- 65 kg）通过结扎冠状动脉并安装脉动式双VAD来建立受损心脏。肝细胞生长因子（HGF）被选择作为血管生成因子的基因，其也具有心脏保护活性。HGF组（n=3）心肌内注射人HGF-cDNA质粒2.0mg。对照组（n=3）同样给予β-半乳糖苷酶质粒。基因转染后四周，所有山羊都试图从VAD中断奶。转染hHGF-cDNA的心肌细胞中hHGF蛋白的表达水平与对照组相比有显著性差异。 ...更多信息转染后3天，S高达1.0+/-0.3ng/g组织。停用VAD后，HGF组血流动力学良好，而对照组血流动力学恶化。肝细胞生长因子组的短缩率显著高于对照组（37. 9 ± 1. 7%vs.26.4 ± 0. 3%，p<0. 01）。对照组左室扩张伴心肌细胞肥大和纤维化改变，而HGF组无此改变。HGF组血管密度明显增加。这些结果表明，使用hHGF的基因治疗可能会提高的机会，“桥恢复”受损的心脏下VAS.Second，我们研究了细胞移植到心肌病的山羊支持左心室辅助装置（LVAD）。4只体重55.7 ± 3.2kg的成年山羊通过输注阿霉素5周来建立心力衰竭。所有山羊均安装搏动性LVAD，维持充分的体循环。其中2只山羊输注体外培养的自体骨髓基质细胞（BMSC）（BMSC组），另2只山羊不输注BMSC（对照组）。所有山羊均持续LVAD支持4周，连续记录心功能和血流动力学变化。BMSC组恢复的心功能（左室射血分数（EF）从39.3+/-2.3%至47.0+/-14.0%）优于对照组（EF从32.6+/-0.7%至26.0+/-4.3%）。结论：在LVAD的支持下，对重度心力衰竭患者进行再生治疗，可能有助于心功能的恢复，增加桥向恢复的可能性。少

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Assessment of ventricular function during YAD support. (Abstract)

YAD 支持期间评估心室功能。

DOI：
发表时间：
2003
期刊：
Int J Artif Organs 26(7)
影响因子：
0
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））

DOI：
发表时间：
2004
期刊：
影响因子：
0
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。

DOI：
发表时间：
2003
期刊：
ASAIO J 49(2)
影响因子：
0
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

Assessment of ventricular function during VAD support. (Abstract)

VAD 支持期间评估心室功能。

DOI：
发表时间：
2003
期刊：
Int J Artif Organs 26(7)
影响因子：
0
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 transfection with human Hepatocyte Growth Factor cDNA plasmid attenuates cardiac re-modeling following acute myocardial infarction in goat hearts implanted with ventricular assist devices.

用人肝细胞生长因子 cDNA 质粒进行基因转染可减弱植入心室辅助装置的山羊心脏急性心肌梗死后的心脏重塑。