Biophysical Mechanisms in two Arhythmogenic Diseases

本项目的重点是两种遗传性心律失常发生机制的生物物理学原理 疾病：致心律失常性右室心肌病(ARVC)和儿茶酚胺能多形性 室性心动过速。在这两种情况下，都会发生心律失常和心脏性猝死(SCO)。 然而，室性心动过速/纤颤(VTA/F)和SCO的具体机制 ARVC或CPVT患者尚未解决。在ARVC中，心律失常可能是由于 由于桥粒蛋白突变导致的心肌细胞之间的机械耦合，这可能导致 间盘功能障碍，以及缝隙连接斑块的最终破裂，心肌细胞死亡和 纤维脂肪替代品。在CPVT中，心律失常是由于渗漏引起的钙调节异常的结果 肌浆网中突变的Ryanodine 2型受体通道。然而，目前还不清楚 心律失常起源于三维心肌或更孤立的索状浦肯野网络。 我们的一般假设是，无论心律失常是由什么机制(S)触发的 和CPVT，VTA/F机制的最终共同途径是波破裂和再入。这个 该项目结合了细胞培养、光学测绘、组织病理学、免疫组织化学和 计算机建模以提供关于结构或钙离子如何变化的可测试预测 调节蛋白转化为电异常，最终导致VTA/F和SCO。我们 提出四个具体目标：1)确定成纤维细胞替代的电生理后果 心肌细胞和细胞间偶联的改变及其在心肌梗死发生中的作用 在ARVC中重新进入。2)确定改变在细胞间偶联和纤维脂肪中的单独作用 右室发育不良3D模型中心律失常发生的沉积。3)调查 在使用2D模式的生物和数值模型中触发和维持再入的机制 模拟浦肯野网络和浦肯野-肌肉连接的类CPVT突变小鼠细胞。4)至 使用真实感的三维模型研究VT的启动机制和向VF的过渡 类似于CPVT的突变小鼠心脏。这项拟议的工作应该会为心律失常提供新的见解 疾病中导致心脏结构和功能内稳态改变的机制。

This project focuses on biophysical principles of arrhythmogenic mechanisms underlying two inherited diseases: arrhythmogenic right ventricular cardiomyopathy (ARVC) and catecholaminergic polymorphic ventricular tachycardia (CPVT). In both cases, arrhythmias and sudden cardiac death (SCO) develop. However, the specific mechanisms underlying ventricular tachycardia/fibrillation (VTA/F) and SCO in either ARVC or CPVT patients has not yet been resolved. In ARVC, arrhythmias may result from impaired mechanical coupling between cardiomyocytes due to mutations in desmosomal proteins, which may lead to dysfunction of the intercalated disk, and eventual disruption of gap junction plaques, myocyte death and fibro-fatty replacement. In CPVT arrhythmias are the result of abnormal calcium regulation due to leaky mutated ryanodine type-2 receptor channels in the sarcoplasmic reticulum. Yet, it is unknown whether the arrhythmias originate in the 3-dimensional myocardium or in the more isolated, cable-like Purkinje network. Our general hypothesis is that regardless of the mechanism(s) by which arrhythmias are triggered in ARVC and CPVT, the final common pathway in the mechanism underlying VTA/F is wavebreak and reentry. The project combines expertise in cell culture, optical mapping, histopathology, immunohistochemistry and computer modeling to provide testable predictions about how alterations of either structural or Ca2+ regulatory proteins translate into electrical abnormalities that ultimately result in VTA/F and SCO. We propose four Specific Aims: 1) To determine electrophysiological consequences of fibroblast replacement of myocytes and of alterations in intercellular coupling in ventricular constructs and their role in the genesis of reentry in ARVC. 2) To establish the individual roles of alterations in intercellular coupling and fibro-fatty deposits in the genesis of arrhythmias in 3D models of the dysplasic right ventricle. 3) To investigate mechanisms of triggering and maintenance of reentry in biological and numerical models using 2D patterns of CPVT-like mutated mouse cells, mimicking the Purkinje network and the Purkinje-muscle junction. 4) To investigate mechanisms of VT initiation and the transition to VF in simulations using a realistic 3D model of the CPVT-like mutated mouse heart. The proposed work should provide new insight into arrhythmia mechanisms in diseases leading to alterations in the structural and functional homeostasis of the heart.