Arrhythmias in HCM Due to Mutation in cMyBP-C

说明： 一些肌原纤维蛋白的突变被认为是遗传性肥厚性心肌病(HCM)的原因，其中心肌肌球蛋白结合蛋白C(由MYBPC3编码)的突变是最常见的，并且与早期心脏骤停(SCA)的风险增加有关。然而，SCA的原因尚不清楚，也没有观察到一些 表达突变cMyBP-C的患者表现出肥大和功能性后遗症，这是肥厚性心肌病的特征，而其他患者则没有。为了解决这些问题，这个子项目探索了在肥厚性心肌病动物模型中钙离子触发心律失常的机制，并确定了导致疾病临床表现深刻异质性的因素，如肥大和离子通道病变的共表达。具体的假设是：(1)收缩功能障碍、肥大和SCA的严重程度与 CMyBP-C功能障碍的程度，在C末端截断时最大，其中突变蛋白未被合并到肌丝中；(2)/WY6PC3rHCM患者的SCA风险受伴随的促心律失常离子通道多态表达的影响，以及(3)MYBPC3中的HCM突变， 单独或与离子通道的突变/多态相结合，导致SCA的风险增加，而不仅仅是由于肥大。我们将在一系列实验中验证这些假设，在这些实验中，我们研究了hcm突变在活体动物和人类hcm的死后组织中的功能后果。 红心。体内功能分析将包括静息条件下和运动负荷测试时的压力-体积环和心电图；体外功能分析将包括评估兰登多夫灌流心脏的心律失常活动以及分离细胞中的钙处理和动作电位。在转基因动物中，hCM突变体cMyBP-C的可变表达对收缩和电生理功能的影响的时程和可逆性将被研究。在转基因动物中，突变体cMyBP-C的表达由四环素诱导系统控制。这些研究的结果将为揭示由于MYBPC3突变导致的肥厚性心肌病疾病表型的潜在机制提供新的见解。

DESCRIPTION: Mutations in several myofibrillar proteins have been implicated as causes of heritable hypertrophic cardiomyopathies (HCM), and among these, mutations in cardiac myosin binding protein-C (encoded by MYBPC3) are among the most common and have been associated with increased risk for sudden cardiac arrest (SCA) at an early age. However, the cause of SCA is not understood, nor is the observation that some patients expressing mutant cMyBP-C exhibit the hypertrophy and functional sequelae that are characteristic of HCM while others do not. To address these issues, this subproject explores the mechanisms of Ca2+ -triggered arrhythmias in animal models of HCM and also identifies factors such as hypertrophy and co-expression of ion channelopathies that contribute to the profound heterogeneity in the clinical manifestations of disease. The specific hypotheses are: (1) the severity of contractile dysfunction, hypertrophy and SCA stratifies with the degree of cMyBP-C dysfunction, being greatest for C-terminal truncations in which the mutant protein is not incorporated into the myofilaments, (2) the risk of SCA in patients with /WY6PC3rHCM is influenced by the concomitant expression of pro-arrhythmic ion channel polymorphisms, and (3) HCM mutations in MYBPC3, alone or in combination with mutations/polymorphisms in ion channels, cause increased risk of SCA beyond that due to hypertrophy alone. We will test these hypotheses in a series of experiments in which the functional consequences of HCM mutations are studied in living animals and in post-mortem tissue from human HCM hearts. In vivo functional assays will include pressure-volume loops and electrocardiography under resting conditions and during exercise stress testing; in vitro functional assays will include assessment of arrhythmic activity in Langendorff-perfused hearts and both Ca2+ handling and action potentials in isolated cells. The time course and reversibility of effects on contractile and electrophysiological function due to variable expression of HCM mutant cMyBP-C will be studied in transgenic animals in which expression of mutant cMyBP-C is controlled by a tetracycline-inducible system. Results from these studies will provide new insights into the mechanisms underlying disease phenotypes in HCM due to mutations in MYBPC3.