Lipids, Inflammation, and Cardiovascular Risk in Rheumatoid Arthritis

 描述(申请人提供)：与普通人群相比，类风湿关节炎(RA)患者患心脏病的风险是普通人的1.5倍。有效的RA治疗可以减少炎症，如肿瘤坏死因子拮抗剂(抗肿瘤坏死因子)，增加低密度脂蛋白胆固醇(LDL-C)水平，这表明治疗可能会增加心脏病的负担。然而，大型观察性研究表明情况恰恰相反：抗肿瘤坏死因子疗法独立地与降低心脏病风险有关。虽然炎症可以解释这些看似自相矛盾的发现，但确切的机制却鲜为人知。在评估类风湿性关节炎的心脏病风险时，关于风湿科医生应该如何权衡血脂水平的变化与治疗和炎症水平，存在着知识上的差距。这项建议的目的是确定低密度脂蛋白水平升高与抗肿瘤坏死因子治疗减轻炎症相关的临床意义，并直接测试炎症变化与血脂水平变化和心脏病风险的关系。这项研究的中心假设是，减少炎症将与降低类风湿关节炎的心脏病风险相关。我们将进一步确定高级脂蛋白指标，包括载脂蛋白B和A1水平、低密度脂蛋白颗粒大小和高密度脂蛋白功能是否可能是RA患者心脏病风险的更好标记物。本项目的目的是：(1)研究炎症变化与晚期脂蛋白指标变化之间的纵向联系；(2)确定抗肿瘤坏死因子治疗减轻炎症对心脏损伤标志物和血管功能的影响；(3)检测炎症减轻对晚期脂蛋白指标变化的影响，以及与RA心脏病风险的关系。目标1将使用每年从前瞻性纵向RA队列中收集的数据和血液样本进行。将确定连续两年之间炎症发生显著变化的受试者(N=200)，并对他们的血液样本进行炎症标记物、血脂和高级脂蛋白测试。在AIMS 2和AIMS 3中，将招募即将开始抗肿瘤坏死因子治疗的RA患者(N=75)，并前瞻性地研究在开始抗肿瘤坏死因子治疗前以及开始抗肿瘤坏死因子治疗6、12和24周时炎症标志物、常规血脂和高级脂蛋白测定的变化。受试者将接受心脏PET成像，以计算基线和24周的冠状动脉血流储备(CFR)。CFR测量冠状动脉血管功能，是心脏病风险的有效替代标记物。这种方法是创新的，因为它利用类风湿关节炎作为人类炎症模型。在这项实验中，抗肿瘤坏死因子被重新用作减少炎症的干预措施，以研究相关的血脂变化和心脏病风险。这项研究意义重大，因为它可能改变RA心脏病风险评估的方式，通过使用综合血脂测量和炎症水平的综合方法的发展。这项研究的结果也可能对普通人群有影响，在那里，炎症在心脏病风险中起着较小但重要的作用。

 DESCRIPTION (provided by applicant): Patients with rheumatoid arthritis (RA) are at 1.5x risk for heart disease risk compared to the general population. Effective RA therapies which reduce inflammation such as tumor necrosis factor antagonists (anti- TNF), increase levels of low density lipoprotein cholesterol (LDL-C) suggesting that treatment may increase the burden of heart disease. However, large observational studies suggest the opposite: anti-TNF therapies are independently associated with reduced heart disease risk. While inflammation may explain these seemingly paradoxical findings, the exact mechanisms are poorly understood. A gap in knowledge exists regarding how rheumatologists should weigh changes in lipid levels with treatment and level of inflammation when assessing for risk of heart disease in RA. The objective of this proposal is to determine the clinical significance of increased LDL-C levels in associated with reduction in inflammation by anti-TNF therapy, and directly test the association of changes in inflammation with changes in lipid levels and risk of heart disease. The central hypothesis of this study is that reducing inflammation will be associated with reduced heart disease risk in RA. We will further determine whether advanced lipoprotein measures, including apolipoprotein B and A1 levels, LDL particle size and HDL function may be better markers of heart disease risk in RA patients. The Aims of this project are to: (1) study the longitudinal association between changes in inflammation with changes in advanced lipoprotein measures, (2) determine the effect of reducing inflammation with anti-TNF therapy on markers of injury and vascular function in the heart, (3) examine the effect of reducing inflammation on changes in advanced lipoprotein measures, and association with heart disease risk in RA. Aim 1 will be conducted using data and blood samples collected annually from a prospective longitudinal RA cohort. Subjects (N=200) with significant changes in inflammation between two consecutive years will be identified and their blood samples measured for inflammatory markers, lipids and advanced lipoprotein tests. In Aims 2 and 3, RA patients (N=75) about to initiate anti-TNF therapy will be recruited, and prospectively studied for changes in inflammatory markers, routine lipids and advanced lipoprotein measures before and at 6, 12, and 24 weeks after starting anti-TNF. Subjects will undergo cardiac PET imaging to calculate coronary flow reserve (CFR) at baseline and 24 weeks. CFR measures coronary vascular function and is a validated surrogate marker for heart disease risk. This approach is innovative because it leverages RA as a human model of inflammation. In this experiment anti-TNF is repurposed as an intervention to reduce inflammation in order to study associated changes in lipids and risk for heart disease. The study is significant because it may transform the way heart disease risk is assessed in RA, by informing development of an integrated approach using comprehensive lipid measurements and level of inflammation. Results from this study may also have implications for the general population where inflammation has a smaller but significant role in the risk of heart disease.