Circulating sphingolipids and risk and outcomes of ventricular fibrillation

循环鞘脂与心室颤动的风险和结果

• 批准号: 10443558
• 负责人: Rozenn Lemaitre
• 金额: $ 58.25万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-10 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443558
• 关键词: Admission activity; Age; Animal Experiments; Apoptosis; Arrhythmia; Biological; Blood; Brain; Calendar; Carbon; Cardiopulmonary Resuscitation; Cell membrane; Ceramides; County; Data; Erythrocyte Membrane; Erythrocytes; Etiology; Event; Exhibits; Fatty Acids; Frequencies; Functional disorder; Future; Gender; Generations; Glycerol; Heart Arrest; Hospitalization; Hospitals; Human; Incidence; Investigation; Ischemia; Knowledge; Lead; Length; Lipids; Mass Spectrum Analysis; Measures; Medical emergency; Membrane; Membrane Lipids; Methods; Molecular; Outcome; Oxidative Stress; Palmitic Acids; Paramedical Personnel; Pathway interactions; Patients; Phospholipids; Play; Population Control; Prevention; Prognosis; Proxy; Public Health; Reperfusion Therapy; Research; Resuscitation; Risk; Risk Factors; Role; Sampling; Saturated Fatty Acids; Specimen; Sphingolipids; Sphingomyelins; System; Time; Ventricular Fibrillation; Washington; Work; base; cardiovascular health; data repository; disorder risk; drug development; high risk; improved; insight; mortality; new therapeutic target; novel; pi bond; repository; sudden cardiac death

ABSTRACT Sudden cardiac arrest due to ventricular fibrillation (VF-SCA) is a major public health concern, and a leading cause of mortality in the US each year. Even in the setting of the best emergency medical systems, resuscitation efforts fail in most cases, with over 70% mortality. This application seeks to identify novel factors, erythrocyte membrane sphingomyelin and ceramide species, associated with 1) incidence of VF- SCA and 2) resuscitation outcomes following VF-SCA. Emerging evidence from cellular and animal experiments, and our previous work on membrane fatty acids and VF-SCA, lead us to these hypotheses: erythrocyte sphingomyelins and ceramides that contain the saturated fatty acid palmitic acid (16:0), are associated with higher risk of VF-SCA and a lower likelihood of resuscitation after VF-SCA; and erythrocyte sphingomyelins and ceramides that contain a saturated fatty acid with 20 carbons or more (20:0, 22:0 or 24:0), are associated with lower risk of VF-SCA and a greater likelihood of resuscitation. We take advantage of the Cardiac Arrest Blood Study Repository (CABS-R), a unique, ongoing, repository of data and specimens on SCA patients in King County, Washington, and optimized mass spectrometry methods to investigate the associations of erythrocyte membrane sphingomyelins and ceramides with the risk of incident VF-SCA (Aim 1) and with resuscitation outcomes following VF-SCA (Aim 2). To maximize the homogeneity of the SCA outcome, we will limit our investigation to SCA patients found in ventricular fibrillation by the attending paramedics. We will measure 8 primary (15 total) ceramide and sphingomyelin species in 4624 existing erythrocyte membrane samples, including 2312 from VF-SCA cases in CABS-R and 2312 from population controls, frequency- matched to cases on age, gender and calendar year. The investigation of VF-SCA risk (Aim 1) will be conducted in the 2312 VF-SCA cases from CABS-R and the 2312 population controls. For Aim 2, we will use outcome data on the VF-SCA cases from Aim 1 to investigate the associations of sphingomyelin and ceramide species with hospital admission, a proxy for cardiac resuscitation, and with discharge alive from the hospital, a proxy for brain resuscitation. The associations of these novel lipid species with both VF-SCA incidence and resuscitation outcomes will provide insight into biological pathways that influence the risk and outcomes of VF-SCA, inform potential novel prevention efforts and advance research involving treatment of VF-SCA.

抽象的 由于心室纤颤（VF-SCA）引起的突然心脏骤停是一个主要的公共卫生问题，也是领先的 每年美国死亡率的原因。即使在最佳紧急医疗系统的环境中， 在大多数情况下，复苏工作失败，死亡率超过70％。该应用程序旨在识别小说 因素，红细胞膜鞘磷脂和神经酰胺，与1）VF-的发生率有关 SCA和2）VF-SCA之后的复苏结果。来自细胞和动物的新兴证据 实验以及我们以前关于膜脂肪酸和VF-SCA的工作，使我们提出了这些假设： 含有饱和脂肪酸棕榈酸（16：0）的红细胞鞘脂蛋白和神经酰胺是 与VF-SCA的较高风险以及VF-SCA后复苏的可能性较低相关；和红细胞 包包含20碳或更多含有20碳的饱和脂肪酸的鞘脂蛋白和神经酰胺（20：0，22：0或 24：0），与VF-SCA的较低风险和复苏的可能性更大有关。我们接受 心脏骤停血液研究存储库（CABS-R）的优势，这是一个独特的，正在进行的数据存储库 以及华盛顿金县的SCA患者的标本，以及优化的质谱方法 研究红细胞膜鞘磷脂和神经酰胺的关联 事件VF-SCA（AIM 1）和VF-SCA后具有复苏结果（AIM 2）。最大化 SCA结果的均匀性，我们将限制我们的调查到心室中发现的SCA患者 参加护理人员的纤颤。我们将测量8个主要（15）神经酰胺和鞘磷脂 4624种现有的红细胞膜样品中的物种，包括CABS-R中的VF-SCA病例的2312种 2312来自人口控制，频率与年龄，性别和日历年相匹配。这 VF-SCA风险的调查（AIM 1）将在CABS-R的2312例VF-SCA案件中进行。 2312人口控制。对于AIM 2，我们将使用AIM 1到VF-SCA案例的结果数据到 研究鞘胺和神经酰胺物种与住院的关联 心脏复苏，并从医院出院，这是大脑复苏的代理。这 这些新型脂质物种与VF-SCA发病率和复苏结果的关联将会 提供对影响VF-SCA风险和结果的生物学途径的见解，告知潜力 涉及VF-SCA治疗的新型预防工作和提前研究。