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Investigating ventricular arrhythmia development in hypertrophic cardiomyopathy in a mouse model and patient samples

研究小鼠模型和患者样本中肥厚型心肌病室性心律失常的发展

基本信息

批准号：
316865582
负责人：
Dr. Frederik Flenner
金额：
--
依托单位：
Institut für Experimentelle Pharmakologie und Toxikologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/316865582?language=en
关键词：
Investigating ventricular arrhythmia development hypertrophic

项目摘要

Hypertrophic cardiomyopathy (HCM) is one of the most frequently inherited cardiac diseases. Its most prominent feature is a thickening of the left ventricle, which can cause an impairment of the pump function of the heart. Furthermore, HCM patients often suffer from rhythm disturbances in atria as well as ventricles. Ventricular arrhythmias are acutely life-threatening and can occur in patients which had been asymptomatic before. It is unknown how these arrhythmias are elicited. Findings from a study on mice which carry a HCM causing mutation in the gene for cardiac troponin T indicate that an increased myofilament calcium sensitivity, which is caused by the mutation, could be a cause for the arrhythmias. These mice did not have thickened ventricles, but showed an increased susceptibility for arrhythmias when beta-adrenergically stimulated. At the same time, ventricular action potentials were shortened. Cardiac muscle cells and strips isolated from the Mybpc3-KI mouse model used in our laboratory, which is based on a mutation found in patients in the gene encoding cardiac myosin-binding protein C, also showed increased arrhythmia susceptibility when beta-adrenergically stimulated. These mice also display increased myofilament calcium sensitivity, but when they carry the disease-causing mutation homozygously, they develop a thickening of the left ventricle and ventricular action potentials are prolonged. This is contrary to the findings made in the troponin T model and indicates that not all HCM mutations which cause increased myofilament calcium sensitivity do influence ventricular action potentials similarly. Additionally, it seems likely that hearts of homozygous Mybpc3-KI mice undergo changes which additionally influence the action potential. In this project, we want to investigate the characteristics of these changes and evaluate if they contribute to the increased arrhythmia susceptibility or if the increased myofilament calcium sensitivity is sufficient to explain it. For this, it will be helpful that mice which are heterozygous for the Mybpc3 mutation do display an increased calcium sensitivity of the myofilament, but do not develop a thickening of the heart. Our results will be validated in experiments using heart samples of HCM patients. This will help us to find possible causes for the increased incidence of ventricular arrhythmias and to clarify, if these causes are different in patients with and without a thickening of the heart. With the help of this project, we hope to find new effective pharmacological therapies for ventricular arrhythmias.

肥厚性心肌病（HCM）是最常见的遗传性心脏疾病之一。其最突出的特征是左心室增厚，可导致心脏泵功能受损。此外，HCM患者经常出现心房和心室节律紊乱。室性心律失常是严重危及生命的，并可发生在以前无症状的患者。目前尚不清楚这些心律失常是如何引起的。一项对携带HCM导致心肌肌钙蛋白T基因突变的小鼠的研究结果表明，由突变引起的肌丝钙敏感性增加可能是心律失常的一个原因。这些小鼠没有心室增厚，但在β -肾上腺素能刺激下表现出对心律失常的易感性增加。同时，心室动作电位缩短。从我们实验室使用的Mybpc3-KI小鼠模型中分离的心肌细胞和条带（基于在患者中发现的编码心肌肌球蛋白结合蛋白C的基因突变）也显示出β -肾上腺素能刺激时心律失常易感性增加。这些小鼠也表现出肌丝钙敏感性增加，但当它们纯合携带致病突变时，它们会出现左心室增厚和心室动作电位延长。这与肌钙蛋白T模型的结果相反，表明并非所有引起肌丝钙敏感性增加的HCM突变都对心室动作电位产生类似的影响。此外，纯合子Mybpc3-KI小鼠的心脏可能会发生变化，进而影响动作电位。在这个项目中，我们想研究这些变化的特征，并评估它们是否有助于心律失常易感性的增加，或者肌丝钙敏感性的增加是否足以解释心律失常。为此，Mybpc3突变杂合的小鼠确实表现出肌丝对钙的敏感性增加，但不会产生心脏增厚，这将是有帮助的。我们的结果将在HCM患者心脏样本的实验中得到验证。这将有助于我们找到室性心律失常发生率增加的可能原因，并澄清这些原因在有和没有心脏增厚的患者中是否不同。我们希望通过这个项目找到新的有效的药物治疗室性心律失常。