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: 9912062
• 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 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912062
• 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 Occlusions; 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; Time; Tissues; Troponin I; Up-Regulation; Ventricular; Ventricular Fibrillation; Ventricular Tachycardia; Veterans; Work; advanced disease; base; biomarker panel; candidate marker; care burden; circulating biomarkers; coronary thrombus; 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）： 可逆性缺血和心脏骤停的动态重塑室颤 (VF) 导致的心脏骤停 (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、无症状的冠状动脉疾病，许多发生心室颤动的患者没有心肌梗塞的证据，而且我们在患有慢性冬眠心肌的猪身上完成的研究表明，可逆性缺血会导致心肌梗塞。保护心肌细胞免受损伤但增加心脏对自发性心室颤动的脆弱性的内在心肌适应性慢性遥测未能识别表明 ST 变化。缺血，但在室颤前交感神经激活期间显示 QT 缩短和左心室 (LV) 舒张末压升高，这与幸存者不同，并且在 SCA 前一周不存在有限的心肌蛋白质组学分析显示多种减少。与冬眠心肌幸存者中糖酵解酶的上调相反，这些变化可能通过减少糖酵解衍生的来促进致命的室性心律失常。 ATP，打开 ATP 依赖性钾通道（导致 QT 缩短）并降低 SR 钙 ATP 酶活性（升高胞质钙和左心室舒张末压）。我们的中心假设是冠状动脉进展导致缺血诱导的适应。狭窄会导致动态分子重塑，从而暂时增加交感神经激活期间 VT/VF 的脆弱性。我们将首先确定是否存在糖酵解功能障碍（酶活性降低和将评估通过 ICD 从 SCA 中救出的猪的候选血浆生物标志物，以确定它们在 SCA 之前是否存在差异性升高。基于离子流的组织和血液 LC/MS 分析这将使我们能够更全面地识别受损的其他心肌机制，并识别升高的新型循环生物标志物。我们将通过解决两个具体目标来实现这一目标：具体目标 1 - 使用植入式心脏除颤器中止 SCA，确定与存活的动物相比，是否存在不同的缺血诱导的蛋白质重塑。冬眠心肌。 假设 1A - 幸存者中心肌糖酵解酶的活性上调，但在 VT/VF 发生时下调。假设 1B - 冬眠心肌幸存者中糖酵解蛋白和酶活性的减少将伴随着 FDG 摄取的减少与摄取的增加。 假设 1C - 基于发现的标记自由离子流的 LC/MS 组织蛋白质组学分析将鉴定出其他新的新特征。发生 VT/VF 的动物与幸存者相比发生变化的蛋白质变化 - 确定候选生物标志物组还是血清蛋白质组。分析可以识别新的生物标志物，在 SCA 发生之前选择性预测 VT/VF 的风险。 假设 2A - 虽然基于 CK-MB 的组织坏死将不存在，但与幸存者相比，血清 TnI 和 BNP 将在 SCA 发生之前短暂升高。假设 2B - 基于发现的血清蛋白质组学分析将新颖地识别生物标志物，预测 SCA 与存活的冬眠心肌动物的风险。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具有慢性冠状动脉疾病的许多特征的 SCA，识别分子肌细胞重塑的瞬时目标以及可以在事件发生之前预测 SCA 风险的新型循环生物标志物。填补关键的知识空白并改善 SCA 的风险分层和预防。