Plasma Sphingolipids and Subclinical and Clinical Cardiovascular Disease

血浆鞘脂与亚临床和临床心血管疾病

• 批准号: 10201737
• 负责人: Rozenn Lemaitre
• 金额: $ 69.27万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-24 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201737
• 关键词: Address; Aging; Apoptosis; Biological Process; Body mass index; Carbon; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Survival; Ceramides; Characteristics; Clinical; Coronary heart disease; Data; Data Reporting; Diabetes Mellitus; Diet; Echocardiography; Elderly; Ethnic Origin; Ethnic group; Etiology; Fatty Acids; Fibrosis; Future; Gadolinium; Generations; Genetic; Genetic Transcription; Heart failure; Human; Hypertrophy; In Vitro; Lead; Left; Left Ventricular Ejection Fraction; Left Ventricular Mass; Life Style; Magnetic Resonance; Magnetic Resonance Imaging; Measurement; Measures; Medical; Mendelian randomization; Metabolic; Methods; Multi-Ethnic Study of Atherosclerosis; Oxidative Stress; Palmitic Acids; Pathway interactions; Physical activity; Plasma; Prevention; Process; Prospective Studies; RNA; Race; Reactive Oxygen Species; Reporting; Risk; Risk Factors; Role; Sampling; Saturated Fatty Acids; Smoking; Sphingolipids; Sphingomyelins; Time; Ventricular; Ventricular End-Diastolic Volumes; Ventricular Remodeling; base; cardiovascular health; cohort; coronary fibrosis; demographics; dihydroceramide desaturase; experimental study; follow-up; heart imaging; insight; knock-down; new therapeutic target; novel; novel therapeutic intervention; overexpression; pi bond; prospective; sex; time use; transcriptome

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.

抽象的 识别与心脏重塑相关的新的可改变因素可能会带来新的结果 早期预防心力衰竭的治疗方法和机会。我们最近报道了 根据心血管健康研究 (CHS)（一项针对老年人的前瞻性研究）观察到的数据， 血浆神经酰胺（Cer）和鞘磷脂（SM）与心力衰竭的风险相关， 但 Cer 和 SM 物种与饱和脂肪酸 16:0（16 个碳：0 双 键）不同于物种与脂肪酸 20:0、22:0 或 24:0 的关联。主要 当前应用程序的目标是探索观察到的机械基础 Cer 和 SM 与心力衰竭的关系。具体来说，我们的目的是检查血浆 Cer 和 脂肪酸为 16:0、20:0、22:0 和 24:0 的 SM 物种与随时间的变化有关 肥厚的心脏影像学测量（目标 1a）；并检查 Cer 和 SM 的关联 具有纤维化心脏成像测量的物种（目标 1b）。此外，我们将确定代谢 改变人原代心室中 Cer 和 SM 种类的水平和转录效应 心肌细胞（目标 2）。我们将 CHS 关于 Cer 和 SM 以及心力衰竭的调查结果扩展到四个 MESA（动脉粥样硬化多种族研究）中的种族/族裔群体，我们将获得以下证据 使用孟德尔随机化分析因果关系（目标 3）。此外，我们还将确定生活方式和 使用重复测量影响 Cer 和 SM 水平随时间变化的其他因素，以 获取未来预防工作的信息（目标 4）。为了实现研究目标，我们将测量 Cer MESA 现有 5,000 个血浆样本中含有 SM 和 SM，其中包括 4000 个基线样本和 1000 个样本 重复；我们将使用 CHS 中现有的 Cer 和 SM 测量值并获得新的 Cer 和 SM CHS 中 1000 个样品的测量；我们将在心肌细胞中进行有针对性的实验。 该研究将利用现有的、高质量的心脏磁共振（CMR）数据在两个 时间点和 MESA 中的钆增强 CMR 成像；同时存在 Cer 和 SM 数据 CHS 中的点； MESA 和 MESA 中的后续信息、遗传学数据和广泛的协变量数据 CHS。这个综合项目利用了两个大型、独立的队列，并有针对性的体外 在人类心肌细胞中进行实验，系统地定义和验证 Cer 和 SM 的作用 在进展为心力衰竭的过程中。它的成功完成将为机制带来新的见解 和过程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。