心脏电子起搏器时代与生物起搏替代的前沿话题(英文)

Cardiac electronic pacemakers and biological Pacemakers

学术背景:植入电子起搏器是目前治疗症状性缓慢心律失常的主要方法,然而它存在许多缺点。能否利用分子生物学原理发展生物起搏器成为大家关注的热点。通过转染编码If电流的超极化激活环核苷酸门控通道基因,过度表达超极化激活环核苷酸门控通道,增加心脏舒张期内向电流,从而在窦房结被抑制时提供起搏作用,这种利用基因治疗和细胞治疗构建的生物起搏在不久的将来可能会成为电子起搏器最为理想的替代方法。目的:总结超极化激活环核苷酸门控通道基因构建生物起搏的研究进展。检索策略:由该论文的研究人员应用计算机检索Pubmed数据库1979-01/2007-06的相关文献,检索词"hyperpolarization-activated cyclic nucleotide-gated channel;biological pacemaker",并限定文章语言种类为English。共检索到157篇文献,对资料进行初审,纳入标准:①与生物起搏及超极化激活环核苷酸门控通道基因密切相关。②同一领域选择近期发表或在权威杂志上发表的文章。排除标准:重复性研究。文献评价:文献的来源主要是超极化激活环核苷酸门控通道基因的基础实验。所选用的36篇文献中,10篇为综述,其余均为临床或基础实验研究。资料综合:①在4种异构体中超极化激活环核苷酸门控通道1,2,4是心脏中的主要部分,超极化激活环核苷酸门控通道3只在胚胎起搏细胞中有低水平表达。起搏活性小的区域(如心室肌),超极化激活环核苷酸门控通道2的表达占优势;而起搏活性高的区域超极化激活环核苷酸门控通道4的表达占优势。此外,超极化激活环核苷酸门控通道2在整个发育阶段,是心室的主要异构体,超极化激活环核苷酸门控通道2:超极化激活环核苷酸门控通道4的相当表达量在乳鼠为5:1,成年鼠为13:1。②超极化激活环核苷酸门控通道通道缺陷可导致病窦综合征。③到目前为止,转染编码If电流的超极化激活环核苷酸门控通道基因被认为是最有可能实现生物起搏的。结论:基因治疗和细胞治疗必将成为改善生物"起搏"功能最理想的方法,以超极化激活环核苷酸门控通道基因和细胞为主的生物起搏在缓慢性心律失常治疗中必将占有一席之地。

BACKGROUND： The implantation of electronic devices has become the preferred treatment for symptomatic bradyarrhythmias. However, there are many shortcomings in electronic pacemakers. The usage of molecular biology principle to develop biological pacemaker has become a topic of discussion in research. When sinoatrial node is inhibited, pacemaker effect runs by transfecting hyperpolarization-activated cyclic nucleotide-gated （HCN） channel gene of If current, overexpressing HCN, and increasing inward current in diastolic phase of the heart. Construction of biological pacemakers by gene therapy and cell therapy may become an optimal substitute of electronic pacemakers in the near future. OBJECTIVE： To sum up the research advancement in application of HCN channel gene to the development of biological pacemaker. RETRIEVAL STRATEGY： The relevant articles published between January 1979 and June 2007 were searched for in Pubmed database by researcher of this article with the key words of ＂hyperpolarization-activated cyclic nucleotide-gated channel, biological pacemaker＂ in English. 157 articles were selected and reviewed by the inclusive criteria of （1） articles closely related with the application of HCN to the development of biological pacemaker; （2）the late articles and articles in authority journals in the same field. Exclusive criterion： repetitive studies. LITERATURE EVALUATION： The main sources of literatures were randomized clinical trial （RCT） on biological pacemaker by HCN. Among 36 selected articles, 10 were reviews, and others were elementary experimental studies. DATA SYNTHESIS： （1）Of all four HCN isoforms, HCN1, HCN2, and HCN4 are the main isoforms in the heart. HCN3 only expresses in embryonic pacemaker cells in a low level. HCN2 highly expressed in low pacing regions （ventricular muscle）, whereas HCN4 highly expressed in high pacing regions, Moreover, HCN2 are the main isoforms in the ventricle. Expression ratio of HCN2 to HCN4 is 5：1 in neonate rats and 13：1 in adult rats. （2）Defects in HCN channels may underlie sick-sinus syndrome. （3）Up to now, HCN genes of If current contribute importantly to the generation of the regular pacemaker potential. CONCLUSION： Gene therapy and cell therapy have become an optimal approach to improve biological pacemakers. Application of HCN channel gene in development of biological pacemaker may hold great promise in the treatment of chronic arhythmia.