Therapeutic safety of high myocardial expression levels of the molecular inotrope S100A1 in a preclinical heart failure model.
Therapeutic safety of high myocardial expression levels of the molecular inotrope S100A1 in a preclinical heart failure model.
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DOI：
10.1038/gt.2013.63
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发表时间：
2014-02
期刊：
影响因子：
5.1
通讯作者：
Pleger, S. T.
中科院分区：
文献类型：
--
作者：
Weber, C.;Neacsu, I.;Krautz, B.;Schlegel, P.;Sauer, S.;Raake, P.;Ritterhoff, J.;Jungmann, A.;Remppis, A. B.;Stangassinger, M.;Koch, W. J.;Katus, H. A.;Mueller, O. J.;Most, P.;Pleger, S. T.
低水平的分子肌力调节剂S100A1足以挽救缺血后心力衰竭(HF)。作为临床应用的前提和确定心肌S100A1 DNA治疗的安全性，我们在一个临床前的大动物心力衰竭模型上研究了高水平的心肌S100A1表达对心脏收缩功能和心律失常发生的影响。在心肌梗死后2周，家猪出现明显的左心室收缩功能障碍。经心前静脉逆行注射AAV6-S100A1(1.5×1013TVP)后，心肌组织中S100A1蛋白的高表达达对照的95倍。在14周时，高水平心肌S100A1蛋白过度表达的猪在心电图上没有表现出异常。电生理右室刺激排除了单形性室性心律失常易感性增加的可能性。高水平的S100A1蛋白在左室心肌的过度表达导致左心室射血分数(LVEF)的显著增加，尽管程度低于先前报道的低水平的S100A1蛋白过表达。然而，心脏重塑也同样逆转。在体内，高表达的心肌S100A1蛋白既不会增加心律失常的发生，也不会对心肌收缩功能造成不良影响。相反，这项研究使用临床前的大型动物模型证明了S100A1基因治疗缺血后心力衰竭的广泛治疗范围。
Low levels of the molecular inotrope S100A1 are sufficient to rescue post-ischemic heart failure (HF). As a prerequisite to clinical application and to determine the safety of myocardial S100A1 DNA-based therapy, we investigated the effects of high myocardial S100A1 expression levels on the cardiac contractile function and occurrence of arrhythmia in a preclinical large animal HF model. At 2 weeks after myocardial infarction domestic pigs presented significant left ventricular (LV) contractile dysfunction. Retrograde application of AAV6-S100A1 (1.5 × 1013 tvp) via the anterior cardiac vein (ACV) resulted in high-level myocardial S100A1 protein peak expression of up to 95-fold above control. At 14 weeks, pigs with high-level myocardial S100A1 protein overexpression did not show abnormalities in the electrocardiogram. Electrophysiological right ventricular stimulation ruled out an increased susceptibility to monomorphic ventricular arrhythmia. High-level S100A1 protein overexpression in the LV myocardium resulted in a significant increase in LV ejection fraction (LVEF), albeit to a lesser extent than previously reported with low S100A1 protein overexpression. Cardiac remodeling was, however, equally reversed. High myocardial S100A1 protein overexpression neither increases the occurrence of cardiac arrhythmia nor causes detrimental effects on myocardial contractile function in vivo. In contrast, this study demonstrates a broad therapeutic range of S100A1 gene therapy in post-ischemic HF using a preclinical large animal model.
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影响因子：
4.8
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