Myocardial functional recovery after fibroblast growth factor 2 gene therapy as assessed by echocardiography and magnetic resonance imaging
Myocardial functional recovery after fibroblast growth factor 2 gene therapy as assessed by echocardiography and magnetic resonance imaging
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DOI：
10.1016/s0003-4975(02)03736-0
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发表时间：
2002-08-01
影响因子：
4.6
通讯作者：
Fullerton, DA
中科院分区：
文献类型：
--
作者：
Horvath, KA;Doukas, J;Fullerton, DA
背景资料。尽管已经证明基因治疗能够在缺血心肌中诱导新生血管，但这种治疗性血管生成的功能意义仍不确定。本研究的目的是调查一种新的成纤维细胞生长因子2(FGF2)基因制剂促进新生血管的能力与其恢复心肌功能的能力之间是否存在实验联系。成纤维细胞生长因子2基因通过构建在胶原基基质中的腺病毒载体来传递，以提供局部和持续的基因活性。采用慢性心肌缺血模型，动物被随机分为缺血区注射腺病毒载体-FGF2治疗组和不治疗组。通过静息和多巴酚丁胺负荷超声心动图以及对比剂增强和电影磁共振成像扫描来评估左心功能。治疗后6周重复研究。动脉形成通过量化治疗区域存在的总动脉壁面积，使用抗α-肌动蛋白免疫组织化学和随后的形态计量学分析来评估。超声心动图结果显示FGF2基因治疗区域的心肌功能显著恢复(治疗前为0.38+/-0.08 cm，治疗后为0.76+/-0.09 cm；p<；0.05)。通过比较FGF2基因治疗的动物和对照组动物的缺血区，以及比较单个动物的缺血区和非缺血区，电影磁共振成像证实了这种功能的改善，其中68%(147/216)的治疗节段室壁运动有所改善，而未治疗的节段没有变化。成纤维细胞生长因子2基因治疗也促进了缺血区内动脉的形成，因为FGF2基因治疗的动物显示存在的小动脉壁总面积比对照组增加了340%。使用基因激活基质的FGF2基因递送方法可以恢复缺血心肌的功能。由于FGF2基因治疗导致动脉生成增加，导致这一心肌功能的恢复。
Background. Although it has been shown that gene therapy is capable of inducing neovascularization in ischemic myocardium, the functional significance of such therapeutic angiogenesis remains less certain. The purpose of this study was to investigate whether an experimental link could be made between the ability of a novel fibroblast growth factor 2 (FGF2) gene formulation to promote neovascularization, and its ability to restore myocardial function.Methods. Fibroblast growth factor 2 gene was delivered by means of an adenovirus vector formulated in a collagen-based matrix to provide localized and sustained gene activity. Using a model of chronic myocardial ischemia, animals were randomized to either treatment of the ischemic area by injections of adenovirus vector-FGF2 or no treatment. Left ventricular function was assessed by rest and dobutamine stress echocardiography as well as contrast-enhanced and cine magnetic resonance imaging scans. Studies were repeated 6 weeks after treatment. Arteriogenesis was assessed by quantifying the total arteriolar wall area present in treated areas, using anti-alpha-actin immunohistochemistry and subsequent morphometric analyses.Results. Echocardiographic results demonstrated a significant restoration of myocardial function in FGF2 gene-treated areas as measured by myocardial wall thickening (0.38 +/- 0.08 cm pretreatment versus 0.76 +/- 0.09 cm posttreatment; p < 0.05). This was demonstrated by comparing the ischemic zones of FGF2 gene-treated versus control-treated animals, as well as by comparing ischemic with nonischemic zones in individual animals This functional improvement was confirmed by cine magnetic resonance imaging, in which 68% (147 of 216) of the treated segments showed improvement in wall motion and there was no change in the untreated segments. Fibroblast growth factor 2 gene treatment also enhanced arteriogenesis within the ischemic zone, as FGF2 gene-treated animals showed a 340% increase in the total arteriolar wall area present versus control-treated animals.Conclusions. The function of ischemic myocardium can be restored by a novel FGF2 gene delivery method using a gene-activated matrix. The increased arteriogenesis as a result of FGF2 gene therapy leads to restoration of this myocardial function.