Conduction System Remodeling After Myocardial Infarction

心肌梗塞后传导系统重塑

• 批准号: 7686579
• 负责人: TERRENCE Xavier O'BRIEN
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686579
• 关键词: Actins; Adenovirus Vector; Adrenergic beta-Antagonists; Adult; Affect; Anatomy; Angiotensin-Converting Enzyme Inhibitors; Aorta; Biological Assay; Birds; Cardiac; Cardiac Myocytes; Cardiac conduction system; Cardiomyopathies; Cardiovascular system; Cell Count; Cell Size; Cells; Cessation of life; Clinical; Connexin 43; Data; Dependency; Development; Dilated Cardiomyopathy; Disease; Disease model; Dose; Echocardiography; Electrocardiogram; Enzyme Inhibition; Failure; Funding; Gap Junctions; Genetic; Genetic Models; Health; Heart Diseases; Heart Hypertrophy; Heart failure; Hypertrophy; In Vitro; Infarction; Knockout Mice; LacZ Genes; Lead; Left; Left ventricular structure; Location; Maintenance; Measures; Methods; Modeling; Molecular; Molecular Biology; Morbidity - disease rate; Morphology; Mouse Strains; Mus; Myocardial Contraction; Myocardial Infarction; Myocardial Ischemia; Myocardium; Operative Surgical Procedures; Outcome; Pathology; Peptidyl-Dipeptidase A; Peripheral; Phenotype; Population; Process; Regulation; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Staging; Stimulus; Symptoms; System; Systems Development; Systolic heart failure; Techniques; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Transgenic Organisms; United States; Ventricular; Ventricular Arrhythmia; Ventricular Remodeling; Veterans; Work; adenoviral-mediated; clinically relevant; constriction; enhanced green fluorescent protein; experience; genetic manipulation; hemodynamics; improved; in vivo; insight; interest; mortality; novel; novel strategies; overexpression; pressure; programs; promoter; public health relevance; research study; response; transcription factor; vector

DESCRIPTION (provided by applicant): The cardiac peripheral conduction system (PCS) is responsible both for the coordination of cardiac contraction as well as being the origin and conduit for abnormal ventricular arrhythmias. We have developed a relevant murine myocardial infarction model, have a novel cardiomyocyte marker for the PCS using Cx40EGFP/+ transgenic which directs Enhanced Green Fluorescent Protein (EGFP) to the cardiac conduction system without affecting the wild-type phenotype (Miquerol, 2004). We have also established endpoints for the PCS phenotype: Connexin40 (specific for the PCS), cardiomyocyte size, hypertrophic response to hemodynamic load and Nkx2-5 (a cardiac transcription factor in PCS cells). Three hypotheses and specific aims are proposed: SA1 Hypothesis: That the peripheral conduction system has a maladaptive hypertrophic response after myocardial infarction (MI). SA2 Hypothesis: Reverse remodeling of the infarcted left ventricle pharmacologically will also remodel the peripheral conduction system. SA3 Hypothesis: Genetic manipulation (reduction) of the peripheral conduction system will reduce the adaptive hypertrophic phenotype. The first aim will use a post-myocardial infarction time course with the Cx40EGFP/+ transgenic line and controls to determine changes in the PCS phenotype during the ventricular remodeling post-MI. SA1: Determine the hypertrophic response of the peripheral conduction system after myocardial infarction in terms of cell size, gap junction morphology and cardiomyocyte peripheral conduction system markers. The second specific aim will compare the PCS phenotype and response to pharmacologic therapy with 2-blockade, angiotensin converting enzyme inhibition or both. SA2: Determine the peripheral conduction system response to reverse pharmacologic remodeling using myocardial infarction and dilated non-ischemic cardiomyopathy models. The third specific aim focuses on mechanism with a Nkx2-5+/- transgenic which reduces the number of cardiomyocytes in the PCS. We also propose to manipulate isolated murine cardiomyocytes by over- expressing Nkx2-5 using adenoviral vectors to determine regulatory mechanisms. SA3: Genetically reduce the number of PCS cardiomyocytes using the Nkx2-5+/- haploinsufficient transgenic line crossed with the Cx40EGFP/+ line to directly measure the effect of both decreased Nkx2-5 and of PCS cell number post-myocardial infarction. Relevance: Heart failure and conduction disease after MI are major health issues. PUBLIC HEALTH RELEVANCE: The cardiac peripheral conduction system is responsible both for the coordination of cardiac contraction as well as being the origin and conduit for abnormal ventricular arrhythmias. The advent of cardiovascular molecular biology has gathered fresh impetus into unraveling the molecular processes that regulate the genesis and integration of peripheral conduction system cardiomyocytes. This proposal takes advantage of techniques and findings of the previous funding period to examine directly the effects of myocardial infarction and systolic heart failure on the cardiac peripheral conduction system at the cellular level. Heart disease involving the cardiac conduction system is one of the leading causes of morbidity and mortality in the Veteran population and in the United States as a whole. Myocardial infarction and heart failure affect the conduction system and may lead to ventricular arrhythmias and/or inefficient myocardial contraction (i.e., dyssynchrony). This proposal's novel approach is to focus on changes in molecular anatomy in the peripheral conduction system in relevant disease models of myocardial infarction and failure, including creating myocardial infarction in transgenic mice strains that readily identify conduction system cells.

描述（由申请人提供）： 心脏外周传导系统（PC）既负责心脏收缩的协调，又是异常心律不齐的起源和管道。我们已经开发了一种相关的鼠心肌梗塞模型，使用CX40EGFP/+转基因为PC具有新颖的心肌细胞标记，该标记将增强的绿色荧光蛋白（EGFP）引向心脏传导系统，而不会影响野生型表型（Miquerolol，2004）。我们还建立了PCS表型的终点：Connexin40（特定于PC），心肌细胞大小，对血液动力学负荷和NKX2-5（PCS细胞中的心脏转录因子）的肥大反应。提出了三个假设和特定目的：SA1假设：心肌梗塞（MI）后外周传导系统具有不良适应性肥大反应。 SA2假设：梗塞左心室药理的反向重塑也将重塑外围传导系统。 SA3假设：周围传导系统的遗传操纵（还原）将减少适应性肥厚的表型。 第一个目标将使用CX40EGFP/+转基因线和对照组使用腰椎后梗塞的时间过程，以确定心室重塑后PCS表型的变化。 SA1：确定心肌梗塞后周围传导系统的肥厚反应，就细胞大小，间隙连接形态和心肌细胞外周传导系统标记物而言。 第二个特定目的将与2块块，血管紧张素转化酶抑制作用或两者兼而有之对PC的表型和对药理治疗的反应。 SA2：使用心肌梗塞和扩张的非缺血性心肌病模型确定外周传导系统对反向药理重塑的反应。 第三个特定目的侧重于NKX2-5 +/-转基因的机制，该机制减少了PC中的心肌细胞数量。我们还建议使用腺病毒载体过度表达NKX2-5来确定调节机制，以操纵分离的鼠心肌细胞。 SA3：使用NKX2-5 +/-单倍弹性的转基因线与CX40EGFP/+线交叉，从遗传上减少PCS心肌细胞数量，以直接测量NKX2-5降低的效果和PCS细胞数量细胞数量后心脏梗死后的效果。 相关性：MI后心力衰竭和传导疾病是主要的健康问题。 公共卫生相关性： 心脏外周传导系统既负责心脏收缩的协调，又是异常心律不齐的起源和管道。心血管分子生物学的出现已经收集了新的动力，以揭开调节外周传导系统心肌细胞的起源和整合的分子过程。该提案利用了先前资助期的技术和发现，直接检查心肌梗塞和收缩性心力衰竭对细胞水平的心脏外周传导系统的影响。 涉及心脏传导系统的心脏病是退伍军人人口和整个美国发病率和死亡率的主要原因之一。心肌梗死和心力衰竭会影响传导系统，并可能导致心室心律不齐和/或效率低下的心肌收缩（即患者同步）。该提议的新方法是专注于心肌梗塞和失败的外周传导系统中分子解剖结构的变化，包括在转基因小鼠菌株中产生心肌梗塞，容易识别传导系统细胞。