HDL Heterogeneity and Function, Statin Therapy, and CVD Outcomes

描述（由申请人提供）：高密度脂蛋白胆固醇携带在高密度脂蛋白颗粒中，这些颗粒在大小、功能和其他特性上是不均匀的。但是高密度脂蛋白胆固醇，由高密度脂蛋白颗粒携带的胆固醇，不能获得与高密度脂蛋白相关的心脏保护作用。最近针对高密度脂蛋白胆固醇的药物失败引起了人们对高密度脂蛋白功能的兴趣。在他汀类药物治疗的背景下，针对HDL的治疗将会增加，但评估他汀类药物对HDL异质性和功能影响的数据很少。本研究的目的是通过验证与高密度脂蛋白功能和颗粒异质性相关的新型分析方法与前瞻性确定的CVD结果的关系，提高我们对HDL功能的理解，并评估他汀类药物治疗对两项具有里程碑意义的他汀类药物试验（JUPITER和TNT）的影响。我们建议测量HDL功能的两个关键新兴指标：1)胆固醇外排，这是HDL通过接受巨噬细胞的胆固醇来促进逆向胆固醇运输的能力，以及2)HDL在防止LDL氧化中的抗炎能力。此外，我们还建议使用两种新技术来测量HDL的大小和亚类异质性，这些技术可以根据大小（离子迁移率和核磁共振波谱）将HDL分成亚类。到目前为止，还没有研究前瞻性地验证这些提议的HDL功能分析与CVD事件的关联，也没有评估他汀类药物治疗如何改变这些关联。为了阐明这些重要问题，我们将开展两项前瞻性病例队列研究，在JUPITER试验中招募了17802名慢性炎症的一级预防患者，在TNT试验中招募了1001名稳定冠状动脉疾病的二级预防患者（共784例心血管疾病事件）。该研究设计具有前瞻性，将回答以下问题：1)HDL功能、HDL颗粒异质性、HDL胆固醇和载脂蛋白A-I之间的关系；2)他汀类药物的影响

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.