HDL Heterogeneity and Function, Statin Therapy, and CVD Outcomes

HDL 异质性和功能、他汀类药物治疗和 CVD 结果

基本信息

批准号：
8590899
负责人：
SAMIA MORA
金额：
$ 41.98万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-22 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8590899
关键词：
Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein A-I Apolipoproteins Biological Assay Biology Blood Vessels Blood specimen Cardiovascular Diseases Cardiovascular system Charge Cholesterol Chronic Clinical Trials Cohort Studies Collaborations Coronary heart disease Data Disease Outcome Dose Double-Blind Method Drug Targeting Evaluation Event Failure Future Genetic Genetic Determinism Genetic Markers Goals Heterogeneity High Density Lipoprotein Cholesterol High Density Lipoproteins Individual Inflammation Inflammatory Intervention Trial Laboratory Research Lipids Lipoproteins Low Density Lipoprotein oxidation Measures Metric Molecular Epidemiology NMR Spectroscopy Nuclear Magnetic Resonance Participant Pathway interactions Patients Pennsylvania Placebos Population Preventive Intervention Primary Prevention Property Randomized Randomized Clinical Trials Recruitment Activity Regimen Research Design Research Infrastructure Role Sample Size Secondary Prevention Techniques Testing Uncertainty Universities atorvastatin base cost cost effective density design experience follow-up insight interest ion mobility macrophage multidisciplinary novel particle prevent prospective public health relevance reverse cholesterol transport rosuvastatin therapy development treatment effect

项目摘要

DESCRIPTION (provided by applicant): HDL cholesterol is carried within HDL particles that are heterogeneous in size, function, and other properties. But HDL cholesterol, the cholesterol carried by HDL particles, does not capture HDL-related cardio-protection. Recent failures of drugs targeting HDL cholesterol have fueled interest in HDL function. Therapies targeting HDL will be added on a background of statin therapy, yet the data evaluating the impact of statins on HDL heterogeneity and function are scarce. The goal of this study is to advance our understanding of HDL function by validating novel assays related to HDL function and particle heterogeneity in relation to prospectively ascertained CVD outcomes, and assess how they are impacted by statin therapy in two landmark statin trials (JUPITER and TNT). We propose to measure two key emerging metrics of HDL function: 1) cholesterol efflux, which is the capacity of HDL to promote reverse cholesterol transport by accepting cholesterol from macrophages, and 2) the anti- inflammatory capacity of HDL in preventing LDL oxidation. Moreover, we also propose to measure HDL size and subclass heterogeneity using two novel techniques that sub-fractionate HDL into subclasses according to size (ion mobility and nuclear magnetic resonance spectroscopy). To date, no study has prospectively validated these proposed HDL functional assays with incident CVD events, nor assessed how these associations may be altered by statin therapy. To elucidate these important questions, we will conduct two prospective case-cohort studies among 17,802 primary prevention individuals recruited on the basis of chronic inflammation in the JUPITER trial, and another 10,001 secondary prevention patients with stable coronary disease in the TNT trial (total 784 CVD events). The study design is prospective and will answer the following questions: 1) What is the relationship between HDL function, HDL particle heterogeneity, HDL cholesterol, and apolipoprotein A-I, 2) What is the influence of statin therapy (in different doses) on HDL function and particle heterogeneity, and 3) What are the associations of HDL function and particle heterogeneity (at baseline and after 1-year of statin or placebo therapy) in relation to CVD events, and how are they altered by statin therapy? Additionally, the availability of extensive biomarker and genetic data already obtained on these participants will allow the unique opportunity to explore multiple mechanistic pathways involved in HDL function at no added cost. Thus, this study will provide important insights into HDL function and particle heterogeneity and how they are impacted by statin therapy in relation to prospectively ascertained CVD outcomes in two landmark statin trials.

描述（由申请人提供）：HDL胆固醇在大小，功能和其他特性异质的HDL颗粒中携带。但是HDL胆固醇是由HDL颗粒携带的胆固醇，不会捕获与HDL相关的心脏保护。针对HDL胆固醇的药物的最新失败引起了对HDL功能的兴趣。靶向HDL的疗法将在他汀类药物疗法的背景下添加，但是评估他汀类药物对HDL异质性和功能的影响的数据很少。这项研究的目的是通过验证与前瞻性确定的CVD结果相关的与HDL功能和粒子异质性相关的新颖测定方法来提高我们对HDL功能的理解，并评估两项具有Landmark statin statin试验中他汀类药物治疗的影响（Jupiter和TNT））。我们建议测量HDL功能的两个关键的新兴指标：1）胆固醇外排，这是HDL通过接受巨噬细胞胆固醇而促进反向胆固醇转运的能力，以及2）HDL在预防LDL氧化方面的抗炎能力。此外，我们还建议使用两种新型技术测量HDL的大小和亚类异质性，这些技术根据大小（ION迁移率和核磁共振光谱）将HDL亚分型HDL分为子类。迄今为止，尚无前瞻性验证这些提出的HDL功能测定法患有事件CVD事件，也没有评估如何通过他汀类药物治疗改变这些关联。为了阐明这些重要问题，我们将在木星试验中根据慢性炎症招募的17,802名原发性预防个体进行两项前瞻性病例研究，另外10,001例TNT试验中的稳定冠状动脉疾病（总计784 CVD）事件）。研究设计是前瞻性的，将回答以下问题：1）HDL功能，HDL粒子异质性，HDL胆固醇和载脂蛋白A-I A-I，2）他汀类药物的影响是什么，是什么关系 HDL功能和粒子异质性的治疗（不同剂量），以及3）与CVD事件有关的HDL功能和粒子异质性的关联（基线和他汀类药物或安慰剂治疗1年之后）是什么相关性的？通过他汀类药物疗法改变？此外，这些参与者已经获得的广泛生物标志物和遗传数据的可用性将允许独特的机会探索HDL功能涉及的多种机械途径，而无需增加成本。因此，这项研究将提供对HDL功能和粒子异质性的重要见解，以及在两项具有里程碑意义的他汀类药物试验中，与前瞻性确定的CVD结局有关他汀类药物治疗的影响。