HDL Heterogeneity and Function, Statin Therapy, and CVD Outcomes

描述(申请人提供)：高密度脂蛋白胆固醇在高密度脂蛋白颗粒中携带，高密度脂蛋白颗粒在大小、功能和其他性质上是不同的。但是，高密度脂蛋白颗粒携带的胆固醇高密度脂蛋白并不能保护高密度脂蛋白相关的心脏。最近针对高密度脂蛋白胆固醇的药物失败激起了人们对高密度脂蛋白功能的兴趣。针对高密度脂蛋白的治疗将在他汀类药物治疗的背景下增加，但评估他汀类药物对高密度脂蛋白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预期确定的心血管疾病结果相关的与高密度脂蛋白功能和颗粒异质性相关的新分析来促进我们对高密度脂蛋白功能的理解，并在两个里程碑式的他汀类试验(Jupiter和TNT)中评估他汀类药物治疗对这些结果的影响。我们建议衡量高密度脂蛋白功能的两个关键指标：1)胆固醇外流，即高密度脂蛋白通过接受巨噬细胞的胆固醇促进胆固醇反向运输的能力；2)高密度脂蛋白在防止低密度脂蛋白氧化方面的抗炎能力。此外，我们还建议使用两种新技术来测量高密度脂蛋白的大小和亚类的异质性，该技术根据大小将高密度脂蛋白细分为亚类(离子迁移率和核磁共振波谱)。到目前为止，还没有研究前瞻性地验证这些建议的高密度脂蛋白功能分析与心血管事件的相关性，也没有评估他汀类药物治疗如何改变这些关联。为了阐明这些重要的问题，我们将在JUPITER试验中招募的17,802名慢性炎症一级预防患者中进行两项前瞻性病例队列研究，并在TNT试验中对另外10,001名稳定性冠状动脉疾病的二级预防患者进行研究(总共784起心血管事件)。这项研究设计是前瞻性的，将回答以下问题：1)高密度脂蛋白功能、高密度脂蛋白颗粒异质性、高密度脂蛋白胆固醇和载脂蛋白A-I之间有什么关系，2)他汀类药物有什么影响 他汀类药物治疗(不同剂量)对高密度脂蛋白功能和颗粒异质性的影响，以及3)高密度脂蛋白功能和颗粒异质性(在基线和他汀类或安慰剂治疗一年后)与心血管事件的关系，以及他汀类药物治疗如何改变它们？此外，已经在这些参与者身上获得的大量生物标记物和遗传数据的获得将使人们有机会在不增加成本的情况下探索与高密度脂蛋白功能有关的多种机制途径。因此，这项研究将在两个里程碑式的他汀类试验中，提供关于高密度脂蛋白功能和颗粒异质性的重要见解，以及他汀类药物治疗与预期确定的心血管疾病结果之间的关系。

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.