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: 9028169
• 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/9028169
• 关键词: Acute; Acute myocardial infarction; Address; Affect; Aftercare; Animal Model; Animals; 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; Individual; Infarction; Injury; Ions; Ischemia; Knowledge; Label; Lead; Left; Left Ventricular Function; Lesion; Link; Minority; Modeling; 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; Risk; Risk Factors; Serum; Stratification; Sudden Death; Survivors; Telemetry; Thrombus; Time; Tissues; Troponin I; Up-Regulation; Ventricular; Ventricular Arrhythmia; 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; molecular dynamics; novel; novel marker; novel strategies; 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）： 可逆性缺血和心脏骤停的动态重构心室颤动（VF）引起的心脏骤停（SCA）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无症状冠状动脉疾病。许多发生VF的患者没有心肌梗死的证据，缺血和SCA之间的联系仍不清楚。我们在慢性冬眠心肌猪中完成的工作表明，可逆性缺血导致内在的心肌适应，保护心肌细胞免受损伤，但增加心脏对自发VF的脆弱性。慢性遥测未能识别指示缺血的ST变化，但已揭示了在VF之前的交感神经激活期间QT缩短和左心室（LV）舒张末期压升高。这与幸存者不同，在SCA前一周不存在。有限的心肌蛋白质组学分析表明，多种糖酵解酶的减少与冬眠心肌幸存者的上调形成对比。这些变化可能通过减少糖酵解来源的ATP、打开ATP依赖性钾通道（导致QT缩短）和降低SR钙ATP酶活性（升高细胞质钙和LV舒张末压）来促进致命性室性心律失常。我们的中心假设是，缺血诱导的适应冠状动脉狭窄的进展导致动态分子重塑，短暂增加的脆弱性VT/VF在交感神经激活。我们将初步确定用ICD从SCA中抢救出来的猪是否存在糖酵解功能障碍（酶活性和PET FDG摄取减少）。将评价最新的血浆生物标志物，以确定它们在SCA之前是否差异性升高。这些研究将与基于发现的蛋白质组学方法互补，该方法采用定量无标记的基于离子电流的LC/MS组织和血液分析。这将使我们能够更完整地鉴定受损的其他肌营养机制，以及鉴定在发生VT/VF的动物中与幸存者相比升高的新型循环血浆生物标志物。我们将通过解决两个具体目标来实现这一点：具体目标1 -使用植入式心脏除颤器中止SCA，确定与冬眠心肌存活的动物相比，是否存在差异性缺血诱导的蛋白质重塑。 假设1A -存活者心肌糖酵解酶活性上调，但在VT/VF发生时下调。 假设1B -糖酵解蛋白和酶活性的减少将伴随着FDG摄取的减少，而冬眠心肌存活者的摄取增加。 假设1C -基于发现的标记自由离子电流的LC/MS组织蛋白质组分析将鉴定在发生VT/VF的动物与存活动物中改变的其他新蛋白质变化。 具体目标2 -确定候选生物标志物组或血清蛋白质组学分析是否可以识别在SCA发生前选择性预测VT/VF风险的新型生物标志物。 假设2A -虽然基于CK-MB的组织坏死将不存在，但与存活者相比，血清TnI和BNP将在SCA之前短暂升高。 假设2B -基于发现的血清蛋白质组分析将鉴定预测SCA风险的新生物标志物，与存活的冬眠心肌动物相比。该项目具有很高的翻译相关性，因为它采用了临床前模型来研究具有许多慢性冠状动脉疾病特征的SCA。识别分子肌细胞重塑的瞬时靶点以及可以在事件发生前预测SCA风险的新型循环生物标志物将填补关键的知识空白，并改善SCA的风险分层和预防。