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

肥厚型心肌病（HCM）是最常见的遗传性心脏病之一。其最显著的特征是左心室增厚，这可能导致心脏泵功能受损。此外，HCM患者经常遭受心房以及心室中的节律紊乱。室性心律失常是急性危及生命的，可发生在以前无症状的患者中。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原因。这些小鼠没有心室增厚，但在β-肾上腺素能刺激时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Mybpc 3-KI小鼠模型中分离的心肌细胞和条，其基于在编码心肌肌球蛋白结合蛋白C的基因中发现的突变，当β-肾上腺素能刺激时，也显示出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，但当它们同源携带致病突变时，它们会出现左心室增厚，心室动作电位延长。这与肌钙蛋白T模型中的发现相反，并表明并非所有导致肌丝钙敏感性增加的HCM突变都会类似地影响心室动作电位。此外，纯合子Mybpc 3-KI小鼠的心脏似乎可能发生额外影响动作电位的变化。在本项目中，我们希望研究这些变化的特征，并评估它们是否有助于增加心律失常的易感性，或者增加的肌丝钙敏感性是否足以解释它。为此，Mybpc 3突变杂合子小鼠确实显示出肌丝钙敏感性增加，但不发展心脏增厚将是有帮助的。我们的研究结果将在使用HCM患者的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。通过本课题的研究，我们希望能为室性心律失常的治疗找到新的有效药物。

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.