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: 10403432
• 负责人: Rozenn Lemaitre
• 金额: $ 69.15万
• 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/10403432
• 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; 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; cardiac magnetic resonance imaging; 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 鉴定与心脏重塑相关的新型可修改因素可能导致新的 治疗方法和早期预防心力衰竭的机会。我们最近报道 从心血管健康研究（CHS）中观察到的数据，这是一项对老年人的前瞻性研究， 血浆神经酰胺（CER）和鞘磷脂（SM）与出现心力衰竭的风险有关 但是CER和SM物种与饱和脂肪酸的关联16：0（16碳：0双 键与脂肪酸20：0，22：0或24：0的键不同。主 该当前应用的目的是探究所观察到的机械基础 CER和SM与心力衰竭的关联。具体而言，我们旨在检查等离子CER和 脂肪酸16：0、20：0、22：0和24：0的SM物种与随着时间的变化有关 肥大的心脏成像测量（AIM 1A）；并检查CER和SM的关联 具有纤维化的心脏成像测量的物种（AIM 1B）。此外，我们将确定代谢 以及改变原发性人心室中CER和SM物种水平的转录效应 心肌细胞（AIM 2）。我们将把CER和SM和心力衰竭的CHS发现扩展到四个 梅萨的种族/种族群体（动脉粥样硬化的多种族研究），我们将获得证据 使用孟德尔随机分析的因果关系（AIM 3）。此外，我们将确定生活方式和 使用重复测量的其他因素会影响CER和SM水平的变化， 获取未来预防工作的信息（AIM 4）。为了解决研究目的，我们将衡量CER 在MESA中有5,000个现有的等离子体样品中的SM，包括4000个基线样品和1000个 重复；我们将在CHS中使用现有的CER和SM测量，并获得新的CER和SM CHS中的1000个样品中的测量；我们将在心肌细胞中进行有针对性的实验。 该研究将利用两个现有的高质量心脏磁共振（CMR）数据 时间点和gadolinium增强了MESA中的CMR成像；一次现有的CER和SM数据 CHS的点；后续信息，遗传学数据和台面和广泛的协变量数据 CHS。这个全面的项目利用了两个大型独立人群，并针对体外 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 在心力衰竭的发展中。它的成功完成将为机制带来新的见解 并在心脏衰竭的早期阶段至关重要的过程，并可以帮助指导未来的新型药物目标 和预防努力。