Circulating sphingolipids and risk and outcomes of ventricular fibrillation

摘要 由于心室纤颤（VF-SCA）引起的心脏骤停是主要的公共卫生问题，并且是主要的健康问题。 美国每年的死亡率。即使在最好的紧急医疗系统中， 复苏努力在大多数情况下失败，死亡率超过70%。本申请寻求鉴定新颖的 因素，红细胞膜鞘磷脂和神经酰胺种类，与1）VF发生率相关- SCA和2）VF-SCA后的复苏结局。来自细胞和动物的新证据 实验，以及我们以前对膜脂肪酸和VF-SCA的研究，使我们得出以下假设： 含有饱和脂肪酸棕榈酸（16：0）的红细胞鞘磷脂和神经酰胺， 与VF-SCA的风险较高和VF-SCA后复苏的可能性较低相关; 鞘磷脂和神经酰胺，其包含具有20个或更多个碳的饱和脂肪酸（20：0、22：0或24：0）， 24：0），与较低的VF-SCA风险和更大的复苏可能性相关。我们采取 心脏骤停血液研究库（CABS-R）的优势，这是一个独特的、持续的数据库 在华盛顿金县的SCA患者的样本，并优化质谱法， 研究红细胞膜鞘磷脂和神经酰胺与 事件VF-SCA（目标1）和VF-SCA后的复苏结局（目标2）。最大化 由于SCA结果的同质性，我们将研究限制在心室肌纤维化中发现的SCA患者。 出现了纤颤我们将测量8种主要（共15种）神经酰胺和鞘磷脂 在4624个现有的红细胞膜样品中，包括2312个来自CABS-R中的VF-SCA病例的样品， 2312例来自人群对照，与年龄、性别和历年病例频率匹配。的 将在CABS-R的2312例VF-SCA病例中进行VF-SCA风险调查（目标1）， 2312人口控制。对于目标2，我们将使用目标1至 研究鞘磷脂和神经酰胺与住院的关系， 心脏复苏，并从医院活着出院，脑复苏的代理。的 这些新的脂质种类与VF-SCA发生率和复苏结果的相关性将 提供对影响VF-SCA风险和结局的生物学途径的深入了解， 新的预防措施和涉及VF-SCA治疗的先进研究。

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.