Circulating sphingolipids and risk and outcomes of ventricular fibrillation

摘要 室颤引起的心脏骤停(VF-SCA)是一个主要的公共卫生问题，也是一个主要的 每年在美国导致死亡的原因。即使在最好的急救医疗系统的背景下， 复苏努力在大多数情况下都失败了，死亡率超过70%。这个应用程序试图识别小说 红细胞膜鞘磷脂和神经酰胺与1)室性心动过速的发生有关。 SCA和2)VF-SCA后复苏结果。来自细胞和动物的新证据 实验，以及我们之前关于膜脂肪酸和VF-SCA的工作，让我们得出了以下假设： 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风险较高和VF-SCA后复苏可能性较低相关；以及红细胞 神经鞘磷脂和神经酰胺含有20个碳或更多的饱和脂肪酸(20：0、22：0或 24：0)，VF-SCA的风险较低，复苏的可能性较大。我们拿着 心脏骤停血液研究资料库(CABS-R)的优势，这是一个独特的、持续的数据资料库 和华盛顿州金县SCA患者的样本，并优化了质谱学方法 探讨红细胞膜鞘磷脂和神经酰胺与糖尿病发病风险的关系 VF-SCA事件(目标1)和VF-SCA后的复苏结果(目标2)。最大限度地提高 SCA结果的同质性，我们的调查将仅限于在脑室发现的SCA患者 主治医生的纤颤。我们将测量8个初级(总共15个)神经酰胺和鞘磷脂 4624例现有红细胞膜样本中的物种，其中2312例来自CABS-R的VF-SCA病例 来自人口控制的2312人，与年龄、性别和日历年的病例频率相匹配。这个 将对来自CABS-R的2312例VF-SCA病例进行VF-SCA风险调查(目标1)和 控制人口2312人。对于目标2，我们将使用目标1至 研究神经鞘蛋白和神经酰胺与住院的关系，神经酰胺和鞘磷脂的代用指标 心脏复苏，出院后还活着，是脑部复苏的指标。这个 这些新的脂质物种与VF-SCA发生率和复苏结果的相关性将 洞察影响VF-SCA风险和结局的生物学途径，告知潜在 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.