Biophysical Mechanisms in two Arhythmogenic Diseases

两种致心律失常疾病的生物物理机制

• 批准号: 7221575
• 负责人: OMER BERENFELD
• 金额: $ 29.96万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7221575
• 关键词: 3-Dimensional; Adherent Culture; Adipose tissue; Arrhythmia; Arrhythmogenic Right Ventricular Dysplasia; Biological; Calcium; Canis familiaris; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Adhesion Molecules; Cells; Cessation of life; Characteristics; Clinical; Collaborations; Complex; Computer Simulation; Condition; Coupling; Cultured Cells; Data; Deposition; Disease; Disruption; Distal; Dysplasia; Extravasation; Fiber; Fibroblasts; Functional disorder; Gap Junctions; Gene Mutation; Generations; Genes; Heart; Histopathology; Homeostasis; Human; Immunohistochemistry; Incidence; Individual; Infiltration; Inherited; Intercalated disc; Ion Channel; Kinetics; Lead; Left; Life; Maintenance; Maps; Mechanics; Modeling; Mus; Muscle; Muscle Cells; Mutate; Mutation; Myocardium; Optics; Pathologic; Pathway interactions; Patients; Pattern; Process; Proteins; Rattus; Regulation; Right ventricular structure; Risk; Role; Ryanodine; Ryanodine Receptor Calcium Release Channel; Safety; Sarcoplasmic Reticulum; Secondary to; Side; Simulate; Site; Source; Staging; Structure; Structure of purkinje fibers; System; Tachycardia; Testing; Thick; Tissues; Translating; Ventricular; Ventricular Fibrillation; Ventricular Tachycardia; Work; base; density; design; desmoplakin; genetic regulatory protein; human disease; insight; mathematical model; monolayer; plakophilins; programs; receptor; research study; simulation; sudden cardiac death; three-dimensional modeling; two-dimensional; vector

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.

该项目的重点是两种遗传性疾病的生物物理学原理 疾病：致心律失常性右心室心肌病（ARVC）和儿茶酚胺能多态性 室性心动过速（CPVT）。在这两种情况下，心律失常和心脏性猝死（SCO）的发展。 然而，室性心动过速/室颤（VTA/F）和SCO的具体机制， ARVC或CPVT患者尚未消退。在ARVC中，心律失常可能由受损的 由于桥粒蛋白突变而导致心肌细胞之间的机械耦合，这可能导致 闰盘的功能障碍，以及间隙连接斑块的最终破坏，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。 肌浆网中突变的兰尼定2型受体通道。然而，目前尚不清楚， 心律失常起源于三维心肌或更孤立的、电缆样浦肯野网络。 我们的一般假设是，无论ARVC中触发心律失常的机制如何， 和CPVT，VTA/F机制中的最后共同通路是波裂和折返。的 该项目结合了细胞培养、光学绘图、组织病理学、免疫组织化学和 计算机建模，以提供可测试的预测，关于结构或Ca2 + 调节蛋白转化为电异常，最终导致VTA/F和SCO。我们 提出了四个具体目的：1）确定成纤维细胞替代的电生理后果， 心肌细胞和心室结构中细胞间偶联的变化及其在心室肌细胞发生中的作用 进入ARVC。2)建立细胞间偶联和纤维脂肪酸改变的个体作用， 沉积物在发育不良右心室的3D模型中的心律失常发生中的作用。3)探讨 用二维模式在生物和数值模式中触发和维持再入的机理 的CPVT样突变小鼠细胞，模仿浦肯野网络和浦肯野肌肉连接。4)到 研究VT启动和过渡到VF的机制，在模拟中使用真实的3D模型， CPVT样突变小鼠心脏拟议的工作应提供新的见解心律失常 导致心脏结构和功能稳态改变的疾病机制。