Arrhythmia Mechanisms in Two Inherited Cardiac Diseases

两种遗传性心脏病的心律失常机制

• 批准号: 8122110
• 负责人: Jose S Jalife
• 金额: $ 202.74万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8122110
• 关键词: Achievement; Action Potentials; Address; Animals; Arrhythmia; Arrhythmogenic Right Ventricular Dysplasia; Attention; Biological; Biomedical Engineering; Biophysics; Cardiac; Cardiac Myocytes; Cause of Death; Clinical; Complex; Coupling; Data; Desmosomes; Development; Diagnosis; Disease; Electrophysiology (science); Environment; Event; Familial disease; Foundations; Funding; Gap Junctions; Gene Mutation; Generations; Genes; Genetic; Heart; Heart Diseases; Heart failure; Human; Individual; Inherited; Interdisciplinary Study; Ion Channel; Knock-in Mouse; Knowledge; Left; Life; Link; Long QT Syndrome; Maintenance; Mathematics; Mediating; Modeling; Molecular; Molecular Biology; Molecular Genetics; Mutation; Myocardial Ischemia; Outcome; Patients; Phenotype; Physiological; Population; Process; Proteins; Research; Research Personnel; Research Project Grants; Right-On; Risk; Simulate; Solid; Source; Structure of purkinje fibers; System; Technology; Testing; Transgenic Model; Translating; United States; Ventricular; Ventricular Tachycardia; Work; base; clinically relevant; experience; genetic regulatory protein; heart electrical activity; heart rhythm; insight; mouse model; mutant; programs; research study; structural biology; sudden cardiac death

DESCRIPTION (provided by applicant): Sudden cardiac death (SCD) caused by arrhythmias is a major cause of death in the United States. In recent years the identification of mutations in proteins that form sarcolemmal ion channels in inherited arrhythmic diseases has greatly contributed to the understanding of the substrate for life-threatening arrhythmias. But many questions remain unanswered. This application for funding of a new program project outlines multidisciplinary research on the arrhythmogenic bases of two different inherited diseases, Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The general objective is to determine how alterations of either structural or Ca2+ regulatory proteins translate into electrical abnormalities that ultimately result in life-threatening arrhythmias and SCD. Experimental and numerical approaches will be used to compare and contrast basic cellular and biophysical alterations underlying the possible arrhythmogenic mechanisms in patients suffering from these devastating diseases. Our proposed strategy derives from the idea that understanding the factors involved in the mechanisms of inherited arrhythmias requires an integrative approach. We have therefore assembled a group of three experimental and theoretical research projects that address fundamental questions on the mechanisms of arrhythmias in ARVC and CPVT. Collaborative work proposed under Projects 1 and 3 seeks to demonstrate that ARVC-relevant mutations that disrupt the integrity of the desmosome carry as a consequence the disruption of the gap junction plaque; and that the disruption of the gap junction plaque impairs the propagation of the cardiac action potential, thus creating a substrate for the generation of cardiac rhythm disturbances. To address the problem of CPVT, Projects 2 and 3 will utilize a unique knock in mouse model that recapitulates the phenotype of CPVT, which is characterized by adrenergically mediated rounds of bidirectional (biVT) and polymorphic (PVT) ventricular tachycardias leading to SCD. Mutually complementary work in both projects will test the hypothesis that biVT and PVT in the mouse model, and by inference in CPVT patients, are triggered by delayed afterdepolarizations (DADs) occurring at Purkinje fibers on the right and left branches of the specialized ventricular conducting system. In both ARVC and CPVT, numerical and biological experiments proposed by Project 3 should provide a solid link between the higher and the lower orders of integration. Accomplishing the work being proposed should provide new insight into fundamental mechanisms leading to complex cardiac rhythms and SCD.

描述（由申请人提供）： 由心律失常引起的心源性猝死（SCD）是美国的一个主要原因。近年来，在遗传性心律失常疾病中形成肌膜离子通道的蛋白质突变的鉴定极大地促进了对危及生命的心律失常的基础的理解。但许多问题仍未得到解答。这项新计划项目的资助申请概述了对两种不同遗传性疾病致心律失常基础的多学科研究，即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（CPVT）。总体目标是确定结构蛋白或 Ca2+ 调节蛋白的改变如何转化为电异常，最终导致危及生命的心律失常和 SCD。将使用实验和数值方法来比较和对比患有这些毁灭性疾病的患者中可能的心律失常机制背后的基本细胞和生物物理变化。我们提出的策略源于这样的想法：了解遗传性心律失常机制中涉及的因素需要采用综合方法。因此，我们组建了一组由三个实验和理论研究项目组成的项目，旨在解决 ARVC 和 CPVT 心律失常机制的基本问题。项目 1 和 3 提出的合作工作旨在证明破坏桥粒完整性的 ARVC 相关突变会导致间隙连接斑块的破坏；间隙连接斑块的破坏会损害心脏动作电位的传播，从而为心律紊乱的产生创造基础。为了解决 CPVT 问题，项目 2 和 3 将利用独特的敲入小鼠模型来概括 CPVT 的表型，其特点是肾上腺素介导的双向 (biVT) 和多形性 (PVT) 室性心动过速，导致 SCD。这两个项目的互补工作将检验以下假设：小鼠模型中的 biVT 和 PVT，以及 CPVT 患者的推断，是由专门心室传导系统左右分支的浦肯野纤维发生的延迟后除极 (DAD) 触发的。在 ARVC 和 CPVT 中，项目 3 提出的数值和生物实验应该在高阶和低阶积分之间提供牢固的联系。完成拟议的工作将为导致复杂心律和 SCD 的基本机制提供新的见解。

项目成果

Plakophilin-2 and the migration, differentiation and transformation of cells derived from the epicardium of neonatal rat hearts.

Plakophilin-2 与新生大鼠心脏心外膜来源的细胞的迁移、分化和转化。

• 发表时间: 2011-08
• 作者: Matthes, Stephanie A;Taffet, Steven;Delmar, Mario
• 通讯作者: Delmar, Mario

The ionic bases of the action potential in isolated mouse cardiac Purkinje cell.

离体小鼠心脏浦肯野细胞动作电位的离子碱基。

• 发表时间: 2013-01
• 影响因子: 5.5
• 作者: Vaidyanathan, Ravi;O'Connell, Ryan P;Deo, Makarand;Milstein, Michelle L;Furspan, Philip;Herron, Todd J;Pandit, Sandeep V;Musa, Hassan;Berenfeld, Omer;Jalife, José;Anumonwo, Justus M B
• 通讯作者: Anumonwo, Justus M B

High-rate pacing-induced atrial fibrillation effectively reveals properties of spontaneously occurring paroxysmal atrial fibrillation in humans.

高速起搏引起的心房颤动有效地揭示了人类自发发生的阵发性心房颤动的特性。

• 发表时间: 2012-11
• 作者: Calvo, David;Atienza, Felipe;Jalife, Jose;Martinez;Bravo, Loreto;Almendral, Jesus;Gonzalez;Arenal, Angel;Bermejo, Javier;Fernandez;Berenfeld, Omer
• 通讯作者: Berenfeld, Omer

Heterogeneity of ATP-sensitive K+ channels in cardiac myocytes: enrichment at the intercalated disk.

心肌细胞中 ATP 敏感 K 通道的异质性：闰盘处的富集。

• 发表时间: 2012-11-30
• 作者: Hong, Miyoun;Bao, Li;Kefaloyianni, Eirini;Agullo;Chkourko, Halina;Foster, Monique;Taskin, Eylem;Zhandre, Marine;Reid, Dylan A;Rothenberg, Eli;Delmar, Mario;Coetzee, William A
• 通讯作者: Coetzee, William A

Ultrastructural changes in cardiac myocytes from Boxer dogs with arrhythmogenic right ventricular cardiomyopathy.

患有致心律失常性右心室心肌病的拳师犬心肌细胞的超微结构变化。

• 发表时间: 2011-06
• 作者: Oxford, Eva M;Danko, Charles G;Kornreich, Bruce G;Maass, Karen;Hemsley, Shari A;Raskolnikov, Dima;Fox, Philip R;Delmar, Mario;Moise, N Sydney
• 通讯作者: Moise, N Sydney