Plasma Sphingolipids and Subclinical and Clinical Cardiovascular Disease

摘要 识别与心脏重塑相关的新的可改变因素可能导致新的 治疗方法和早期预防心力衰竭的机会。我们最近报道 根据心血管健康研究（CHS）中观察到的数据，这是一项针对老年人的前瞻性研究， 血浆神经酰胺（Cer）和鞘磷脂（SM）与心力衰竭的风险有关， 但Cer和SM物种与饱和脂肪酸16：0（16个碳：0双 键）与物种与脂肪酸20：0、22：0或24：0的关联不同。主要 本申请的目的是探索所观察到的 Cer和SM与心力衰竭的相关性。具体来说，我们的目标是检查血浆Cer和 具有脂肪酸16：0、20：0、22：0和24：0的SM种类与以下物质随时间的变化相关： 肥大的心脏成像测量（目的1a）;并检查Cer和SM的相关性 心脏影像学指标为纤维化的种属（目的1b）。此外，我们将确定代谢 改变Cer和SM种类在原代人心室肌细胞中的水平及其转录效应 心肌细胞（Aim 2）。我们将把CHS对Cer、SM和心力衰竭的研究结果扩展到四个 梅萨（多种族动脉粥样硬化研究）中的种族/种族群体，我们将获得以下证据： 使用孟德尔随机化分析的因果关系（目的3）。此外，我们将确定生活方式和 使用重复测量影响Cer和SM水平随时间变化的其他因素， 为今后的预防工作获得信息（目标4）。为了实现研究目的，我们将测量Cer 在梅萨的5，000份现有血浆样本中，包括4000份基线样本和1000份 重复;我们将在CHS中使用现有的Cer和SM测量值，并获得新的Cer和SM 我们将在CHS中进行1000个样本的测量;我们将在心肌细胞中进行靶向实验。 该研究将利用现有的高质量心脏磁共振（CMR）数据， 梅萨中的时间点和钆增强CMR成像;同时获得现有Cer和SM数据 CHS的随访信息、遗传学数据和梅萨和 CHS。这个综合性项目利用两个大型的独立队列， 在人类心肌细胞中进行实验，以系统地定义和验证Cer和SM的作用 在心力衰竭的进展中。它的成功完成将为机制带来新的见解 在心力衰竭的早期阶段至关重要，可以帮助指导未来的新药物靶点 和预防工作。

ABSTRACT Identification of novel modifiable factors associated with cardiac remodeling may lead to new therapeutic approaches and opportunities for early prevention of heart failure. We recently reported from data observed in the Cardiovascular Health Study (CHS), a prospective study of older adults, that plasma ceramides (Cer) and sphingomyelins (SM) were associated with risk of incident heart failure, but the associations of Cer and SM species with the saturated fatty acid 16:0 (16 carbons:0 double bond) differed from the associations of species with the fatty acids 20:0, 22:0 or 24:0. The main objectives of this current application are to probe the mechanistic underpinnings of the observed association of Cer and SM with heart failure. Specifically, we aim to examine whether plasma Cer and SM species with the fatty acids 16:0, 20:0, 22:0 and 24:0 are associated with changes over time in cardiac imaging measures of hypertrophy (Aim 1a); and to examine the associations of Cer and SM species with cardiac imaging measures of fibrosis (Aim 1b). Furthermore, we will determine metabolic and transcriptional effects of altering levels of Cer and SM species in primary human ventricular cardiomyocytes (Aim 2). We will extend the CHS findings on Cer and SM and heart failure to four race/ethnic groups in MESA (Multi-Ethnic Study of Atherosclerosis), and we will gain evidence of causality using Mendelian Randomization analyses (Aim 3). In addition, we will identify life-style and other factors that influence changes in Cer and SM levels over time using repeat measurements, to gain information for future prevention efforts (Aim 4). To address the study aims, we will measure Cer and SM in 5,000 existing plasma samples in MESA, including 4000 baseline samples and 1000 repeats; we will use existing Cer and SM measurements in CHS and obtain new Cer and SM measurements in 1000 samples in CHS; and we will conduct targeted experiments in cardiomyocytes. The study will take advantage of existing, high quality cardiac magnetic resonance (CMR) data at two time points, and gadolinium enhanced CMR imaging in MESA; existing Cer and SM data at one time point in CHS; follow-up information, genetics data and extensive covariate data in both MESA and CHS. This comprehensive project leverages two large, independent cohorts and targeted in vitro experimentation in human cardiomyocytes to systematically define and validate the role of Cer and SM in the progression to heart failure. Its successful completion will bring new insights into mechanisms and processes critical in the early stages of cardiac failure and can help direct future novel drug targets and prevention efforts.