Plasma sphingolipids and risk of cardiovascular disease

 描述(由申请人提供)：本申请寻求确定与发生心力衰竭(HF)、发生房颤(AF)、发生心脏性猝死(SCD)和总死亡率相关的新的可修改因素，即血浆神经酰胺和鞘磷脂种类。神经酰胺和鞘磷脂是细胞和循环中的脂类，参与细胞凋亡、氧化应激、缺血/再灌注等与心力衰竭和心律失常的病理生理相关的机制。直到最近，所有神经酰胺和鞘磷脂都被认为具有相似的生理作用，大多数研究调查了总水平；然而，现在有令人信服的证据表明，携带不同长度饱和脂肪酸的物种表现出不同的生物学活性。这些研究为我们的假设提供了强有力的基础，即携带16：0脂肪酸(16个碳水化合物，0个双键)的血浆神经酰胺和鞘磷脂种类与发生HF、AF和SCD的风险和总死亡率相关；携带20：0、22：0或24：0脂肪酸的血浆神经酰胺和鞘磷脂种类越高，发生HF、AF和SCD的风险越低，总死亡率越低。我们将在心血管健康研究(CHS)中调查这些新的假设，这是一项由NHLBI资助的关于老年人心血管疾病危险因素的前瞻性队列研究。我们将在现有的血浆样品中用液相色谱和质谱法测定神经酰胺和鞘磷脂种类。1992年收集的血浆样本可在约3800名社区卫生服务参与者中获得。我们将把新的数据与现有的关于风险因素的广泛信息和1992年至2011年的后续数据结合起来。在基本目标中，我们将调查血浆神经酰胺和鞘磷脂种类(16：0、20：0、22：0和24：0)与发生心力衰竭(Aim1)、发生房颤(Aim 2)、发生SCD(Aim 3)以及总死亡率和心血管疾病死亡率(Aim 4)的关系。在随访期间，已确认968例心衰、978例房颤、200例SCD和2788例死亡。在次级目标中，我们将调查神经酰胺和鞘磷脂种类与中间终点的关系，包括来自超声心动图的左心室重量、心电图表型，以及左室应激、心肌细胞损伤和炎症的标记物(次级目标1)；我们还将调查神经酰胺和鞘磷脂种类水平的生活方式预测因素，包括药物、饮食因素、吸烟和1992年考试前测量的体力活动(次级目标2)。这项研究将全面检查新的可修饰分子，神经酰胺和鞘磷脂种类，与心衰的发生率和介体，以及心律失常，死亡率， 和生活方式的特点。人们对不同种类的神经纤维素和神经鞘磷脂在人类中的潜在差异影响知之甚少。这项研究将为对抗心力衰竭和心律失常的新药物靶点和新的预防努力提供信息。

 DESCRIPTION (provided by applicant): This application seeks to identify novel modifiable factors, plasma ceramide and sphingomyelin species, associated with risks of incident heart failure (HF), incident atrial fibrillation (AF), incident sudden cardiac death (SCD) and total mortality. Ceramides and sphingomyelins are cell and circulating lipids that are involved in apoptosis, oxidative stress, ischemia/reperfusion and other mechanisms of relevance to the pathophysiology of HF and arrhythmias. Until recently, all ceramides and sphingomyelins were thought to have similar physiological effects and most studies investigated total levels; however, there is now compelling evidence that species that carry saturated fatty acids of different length exhibit divergent biological activities. These studies provide a strong basis for our hypothesis that higher plasma levels of ceramide and sphingomyelin species that carry the fatty acid 16:0 (16 carbons, 0 double bond) are associated with higher risks of incident HF, AF and SCD, and higher total mortality; and higher plasma levels of ceramide and sphingomyelin species that carry the fatty acids 20:0, 22:0 or 24:0 are associated with lower risks of incident HF, AF and SCD, and lower total mortality. We will investigate these novel hypotheses in the Cardiovascular Health Study (CHS), an NHLBI-funded prospective cohort study of risk factors for cardiovascular disease among older adults. We will measure ceramide and sphingomyelin species in existing plasma samples using liquid chromatography followed by mass spectrometry. Plasma samples collected in 1992 are available on about 3800 CHS participants. We will combine the new data with existing extensive information on risk factors and follow-up data from 1992 to 2011. In Primary Aims, we will investigate the associations of plasma ceramide and sphingomyelin species containing 16:0, 20:0, 22:0, and 24:0 with the risks of incident HF (Aim1), incident AF (Aim 2), incident SCD (Aim 3) and with total and cardiovascular disease mortality (Aim 4). During follow-up, 968 incident HF, 978 incident AF, 200 incident SCD and 2788 deaths have been identified. In Secondary Aims, we will investigate the associations of the ceramide and sphingomyelin species with intermediate endpoints including left ventricular mass from echocardiography, electrocardiographic phenotypes, and markers of left ventricular stress, cardiomyocyte injury and inflammation (Secondary Aim 1); we will also investigate life- style predictors of levels of the ceramide and sphingomyelin species, including medications, dietary factors, smoking and physical activity measured before the 1992 exam (Secondary Aim 2). This study will comprehensively examine the associations of novel modifiable molecules, ceramide and sphingomyelin species, with incidence and mediators of HF and arrhythmia, mortality, and life-style characteristics. Little is known about potential divergent effects of distinct ceramde and sphingomyelin species in humans. The study will inform novel drug targets and novel prevention efforts in the fight against HF and arrhythmia.