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.
It is generally believed that higher levels of HDL cholesterol protect against vascular events. This view has been recently challenged by genetic studies and clinical trials that have raised doubt about the protective role of HDL cholesterol. Yet it is likey that other HDL measures that reflect its diverse functions or types are better than HDL cholesterol. In this study, we propose to conduct a comprehensive evaluation of new tests of HDL function and particle subtypes in relation to future vascular events in individuals treated with statin therapy. This will provide important insights into why HDL is protective against vascular events and may identify novel targets of therapy.
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