Dynamic Remodeling From Reversible Ischemia and Sudden Cardiac Arrest

可逆性缺血和心脏骤停的动态重塑

• 批准号: 9206884
• 负责人: John M Canty
• 金额: --
• 依托单位: VA WESTERN NEW YORK HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206884
• 关键词: Acute; Acute myocardial infarction; Address; Affect; Aftercare; Animal Model; Animals; Arterial Fatty Streak; Autopsy; Biological Markers; Blood; Blood flow; Blood specimen; Ca(2+)-Transporting ATPase; Calcium; Cardiac; Cardiovascular Diseases; Cause of Death; Chronic; Clinical; Congestive Heart Failure; Coronary; Coronary Arteriosclerosis; Coronary Stenosis; Coronary artery; Coronary heart disease; Creatine Kinase MB Isoenzyme; Defibrillators; Depressed mood; Devices; Diastolic blood pressure; EFRAC; Enzymes; Evaluation; Event; Exhibits; Family suidae; Frequencies; Generations; Glycolysis; Goals; Healthcare; Heart; Heart Arrest; Heart Diseases; Heart failure; Hospitals; Immunoassay; Impairment; Individual; Infarction; Injury; Ions; Ischemia; Knowledge; Label; Lead; Left; Left Ventricular Function; Link; Minority; Modeling; Molecular; Molecular Target; Muscle Cells; Muscle Proteins; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myocardium; Necrosis; Patients; Plasma; Positron-Emission Tomography; Potassium Channel; Pre-Clinical Model; Precipitating Factors; Prevention; Process; Proteins; Proteomics; Public Health; Resuscitation; Risk; Risk Factors; Risk stratification; Serum; Sudden Death; Survivors; Telemetry; Thrombus; Time; Tissues; Troponin I; Up-Regulation; Ventricular; Ventricular Fibrillation; Ventricular Tachycardia; Veterans; Work; advanced disease; base; biomarker panel; candidate marker; care burden; circulating biomarkers; enzyme activity; functional disability; heart rhythm; high risk; improved; liquid chromatography mass spectrometry; novel; novel marker; novel strategies; predictive marker; protein biomarkers; public health relevance; sarcoplasmic reticulum calcium ATPase; sudden cardiac death; uptake

 DESCRIPTION (provided by applicant): Dynamic Remodeling from Reversible Ischemia and Sudden Cardiac Arrest Sudden cardiac arrest (SCA) from ventricular fibrillation (VF) is a major public health problem affecting Veterans and the majority of victims have severe, asymptomatic coronary artery disease. Many patients developing VF have no evidence of a myocardial infarction and the link between ischemia and SCA remains unclear. Our completed work in swine with chronic hibernating myocardium has demonstrated that reversible ischemia leads to intrinsic myocardial adaptations that protect myocytes from injury yet increase vulnerability of the heart to spontaneous VF. Chronic telemetry has failed to identify ST changes indicative of ischemia but has re- vealed QT shortening and elevated left ventricular (LV) end-diastolic pressure during sympathetic activation immediately preceding VF. This differs from survivors and is not present the week before SCA. Limited myo- cardial proteomic profiling has demonstrated reductions in multiple glycolytic enzymes that contrast with their upregulation in survivors with hibernating myocardium. These changes could promote lethal ventricular ar- rhythmias by reducing glycolytically derived ATP, opening ATP-dependent potassium channels (resulting in QT shortening) and reducing SR calcium ATPase activity (elevating cytosolic calcium and LV end-diastolic pres- sure). Our central hypothesis is that ischemia-induced adaptations resulting from the progression of a coronary stenosis leads to dynamic molecular remodeling that transiently increases the vulnerability to VT/VF during sympathetic activation. We will initially determine whether there is a functional impairment of glycolysis (reduced enzyme activity and PET FDG uptake) in swine rescued from SCA with an ICD. Candi- date plasma biomarkers will be evaluated to identify if they are differentially elevated prior to SCA. These stud- ies will be complimented with discovery-based proteomic approaches employing quantitative label-free ion cur- rent-based LC/MS profiling of tissue and blood. This will allow us to more completely identify additional myo- cardial mechanisms that are impaired as well as identify novel circulating plasma biomarkers that are elevated in animals developing VT/VF vs. survivors. We will accomplish this by addressing two Specific Aims: Specific Aim 1 - Using an implantable cardiac defibrillator to abort SCA, determine whether there is differential ischemia-induced protein remodeling in comparison to animals that survive with hibernating myocardium. Hypothesis 1A - The activity of myocardial glycolytic enzymes is upregulated in survivors but down- regulated at the time that VT/VF develops. Hypothesis 1B - Reductions in glycolytic proteins and enzyme activity will be accompanied by reductions in FDG uptake vs. increased uptake in survivors with hibernating myocardium. Hypothesis 1C - Discovery-based label free ion current-based LC/MS tissue proteomic profiling will identify additional novel protein changes that are altered in animals developing VT/VF vs. survivors. Specific Aim 2 -Determine whether a candidate biomarker panel or serum proteomic profiling can identify novel biomarkers that selectively predict the risk of VT/VF before SCA develops. Hypothesis 2A - While tissue necrosis based on CK-MB will be absent, serum TnI and BNP will be- come transiently elevated prior to SCA as compared to survivors. Hypothesis 2B - Discovery based serum proteomic profiling will identify novel biomarkers predicting the risk of SCA vs. animals with hibernating myocardium that survive. The project has high translational relevance since it employs a preclinical model to study SCA that has many of the features of chronic coronary artery disease. Identifying transient targets of molecular myocyte remodeling as well as novel circulating biomarkers that can predict the risk of SCA before an event would fill a critical knowledge gap and lead to improved risk stratification and prevention of SCA.

 描述（由申请人提供）： 可逆性缺血和心脏突然心脏骤停（SCA）的动态重塑（VF）是影响退伍军人的主要公共卫生问题 大多数受害者患有严重的不对称冠状动脉疾病。许多患者出现VF没有证据表明心肌梗塞，缺血和SCA之间的联系尚不清楚。我们在猪中完成的慢性冬眠心肌的完成工作表明，可逆性缺血会导致内在的心肌适应性，可保护心肌细胞免受损伤，但会增加心脏对发起人VF的脆弱性。慢性遥测未能鉴定出指示缺血的变化，但在交感神经激活期间在VF之前，QT缩短了QT缩短和升高的左心室（LV）末端 - 舒张末压。与幸存者的差异，在SCA之前不存在。有限的肌性蛋白质组学分析表明，多种糖酵解酶的降低与冬眠心肌的幸存者的上调形成对比。这些变化可以通过减少糖酵解衍生的ATP，开放ATP依赖性的钾通道（导致QT缩短）和降低SR钙ATPase活性（升高细胞溶质钙和LV终端 - 抑制剂肯定）来促进致命的心室心律。我们的中心假设是，冠状动脉狭窄的进展引起的缺血诱导的适应性导致动态分子重塑，从而在交感神经激活过程中瞬时增加了对VT/VF的脆弱性。我们最初将确定是否有功能障碍糖酵解（降低的酶活性和PET FDG摄取），并从SCA中救出了ICD。将评估候选血浆生物标志物，以确定它们是否在SCA之前差异升高。这些研究将对基于发现的基于发现的蛋白质组学方法来称赞，采用无定量标记的基于基于cur租赁的LC/MS的LC/MS分析组织和血液。这将使我们能够更彻底地识别受损害的其他肌膜机制，并确定新型的循环等离子体生物标志物，这些循环血浆生物标志物在动物中升高，发展为VT/VF与生存。我们将通过解决两个具体目的来实现这一目标：具体目标1-使用可植入的心脏除颤器中止SCA，确定与动物假说1a相比，是否存在差异性缺血诱导的蛋白质重塑 - 心肌gllycolypolytic酶的活性在生存中却在vt -vt -vff fff fff fff fff fff fff fff fff fff fff fff fff fff fff fff fff fff fff fff fff fff fff fff fff fff fff fff中得到了上调。假设1b-糖酵解蛋白和酶活性的降低将通过降低FDG摄取与增加冬眠心肌的存活的摄取来实现。假设1C-基于发现的标签自由离子基于基于LC/MS组织的蛋白质组学分析将确定其他新型蛋白质变化，这些变化在动物中发生了改变，这些变化发生了VT/VF/VF与生存。特定目标2确定是候选生物标志物面板还是血清蛋白质组学分析可以鉴定出新型的生物标志物，这些新型生物标志物有选择地预测SCA开发前VT/VF的风险。假设2a-尽管将不存在基于CK-MB的组织坏死，但与存活相比，SCA之前的血清TNI和BNP将暂时升高。假设2b-基于发现的血清蛋白质组学分析将确定新型的生物标志物，可预测SCA与动物的风险，并具有冬眠的心肌。该项目具有很高的转化相关性，因为它采用临床前模型来研究SCA，具有慢性冠状动脉疾病的许多特征。识别分子肌细胞重塑的瞬态靶标以及新的循环生物标志物，可以在事件发生之前预测SCA的风险，这将填补关键的知识差距，并改善SCA的风险分层和预防。