Plasma sphingolipids and risk of cardiovascular disease

 描述（由申请方提供）：本申请旨在确定与突发心力衰竭（HF）、突发房颤（AF）、突发心源性猝死（SCD）和总死亡率风险相关的新型可改变因素，即血浆神经酰胺和鞘磷脂物质。神经酰胺和鞘磷脂是细胞和循环脂质，参与细胞凋亡、氧化应激、缺血/再灌注以及与HF和心律失常的病理生理学相关的其他机制。直到最近，所有神经酰胺和鞘磷脂被认为具有相似的生理效应，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活性。这些研究为我们的假设提供了强有力的依据，即携带脂肪酸16：0（16个碳，0个双键）的神经酰胺和鞘磷脂物质的血浆水平较高与HF、AF和SCD事件的风险较高以及总死亡率较高相关;携带脂肪酸20：0、22：0或24：0的神经酰胺和鞘磷脂物质的血浆水平较高与HF、AF和SCD事件的风险较低以及总死亡率较低相关。我们将在心血管健康研究（CHS）中调查这些新的假设，CHS是一项由NHLBI资助的老年人心血管疾病危险因素的前瞻性队列研究。我们将使用液相色谱法和质谱法测量现有血浆样本中的神经酰胺和鞘磷脂物质。1992年收集的血浆样本可用于约3800名CHS参与者。我们将联合收割机结合新的数据与现有的风险因素和1992年至2011年随访数据的广泛信息。在主要目的中，我们将研究含有16：0、20：0、22：0和24：0的血浆神经酰胺和鞘磷脂物质与HF事件（目的1）、AF事件（目的2）、SCD事件（目的3）风险以及总死亡率和心血管疾病死亡率（目的4）的相关性。在随访期间，确定了968例HF事件、978例AF事件、200例SCD事件和2788例死亡。在次要目的中，我们将研究神经酰胺和鞘磷脂与中间终点的关系，包括超声心动图的左心室质量、心电图表型和左心室应激标志物、心肌细胞损伤和炎症（第二目标1）;我们还将调查神经酰胺和鞘磷脂类物质水平的生活方式预测因子，包括药物，饮食因素，1992年考试前测量的吸烟和身体活动（次要目标2）。本研究将全面检查新型可修饰分子神经酰胺和鞘磷脂与HF和心律失常的发病率和介导物、死亡率， 和生活方式的特点。关于不同的神经酰胺和鞘磷脂物质在人体中的潜在不同作用，我们知之甚少。该研究将为对抗HF和心律失常的新型药物靶点和新型预防工作提供信息。

 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.