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: 10646441
• 负责人: Rozenn Lemaitre
• 金额: $ 68.1万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646441
• 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 Population; Etiology; Fatty Acids; Fibrosis; Future; Gadolinium; Generations; Genetic; Genetic Transcription; Heart failure; Human; Hypertrophy; In Vitro; 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; cardiac magnetic resonance imaging; cardiovascular health; cohort; coronary fibrosis; demographics; dihydroceramide desaturase; experimental study; fatty acylation; follow-up; heart imaging; insight; knock-down; new therapeutic target; novel; novel therapeutic intervention; overexpression; pi bond; prospective; racial population; 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.

摘要 识别与心脏重构相关的新的可修改因子可能导致新的 早期预防心力衰竭的治疗方法和机会。我们最近报道了 从心血管健康研究(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)与发生心力衰竭的风险相关， 而Cer和Sm物种与饱和脂肪酸16：0(16个碳：0)的关系 键)不同于物种与脂肪酸20：0、22：0或24：0的关联性。主 目前这一应用的目的是探索观察到的 Cer和SM与心力衰竭的关系。具体地说，我们的目标是检查血浆Cer和 含有16：0、20：0、22：0和24：0脂肪酸的SM物种与随时间的变化有关 肥厚的心脏影像测量(目标1a)；并检查Cer和SM的相关性 有心脏成像措施的纤维化物种(目标1b)。此外，我们将确定新陈代谢 Cer和Sm基因在人原代心肌细胞中的转录效应 心肌细胞(目标2)。我们将把CHS关于CER和SM以及心力衰竭的调查结果扩大到四个 在MESA(动脉粥样硬化的多民族研究)中的种族/民族，我们将获得证据 使用孟德尔随机化分析的因果关系(目标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，以 为今后的预防工作获取信息(目标4)。为了达到研究的目的，我们将测量Cer 在梅萨现有的5000个血浆样本中，包括4000个基线样本和1000个样本中的SM 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 在CHS的1000个样本中进行测量；我们将在心肌细胞中进行有针对性的实验。 这项研究将利用现有的、高质量的心脏磁共振(CMR)数据 在台地的时间点和Gd增强的CMR成像；同时存在Cer和SM数据 CHS中的点；MESA和MESA中的随访信息、遗传学数据和广泛的协变量数据 CHS.这一全面的项目利用了两个大型、独立的队列，并在体外定向 人心肌细胞系统确定和验证Cer和SM作用的实验 在心力衰竭的过程中。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，并有助于指导未来的新药物靶点 和预防工作。

项目成果

Very long-chain saturated fatty acids and diabetes and cardiovascular disease.

• DOI: 10.1097/mol.0000000000000806
• 发表时间: 2022-02-01
• 期刊: Current opinion in lipidology
• 影响因子: 4.4
• 作者: Lemaitre RN;King IB
• 通讯作者: King IB