Cardiovascular Inflammation Reduction Trial (CIRT) - Inflammation Imaging Study

 描述(申请人提供)：血管炎症是动脉粥样硬化的中心特征，与斑块的起始、持续和不稳定有关。目前尚不清楚的是，通过不改变动脉粥样硬化过程中其他原因途径的干预措施来减少血管炎症是否可以减少未来的心血管事件。NHLBI资助(Ridker 5U01HL101422)的心血管炎症减轻试验(CIRT)调查了小剂量甲氨蝶呤(LDM)是否可以降低既往心肌梗死患者的心血管发病率和死亡率。为了确认CIRT试验背后的主要作用机制，纳入血管炎症成像的测量是至关重要的。18-氟代脱氧葡萄糖正电子发射断层扫描/计算机断层扫描(18-FDG-PET/CT)已被证实是一种可重复性的血管炎症指标，与斑块巨噬细胞含量、众多循环炎症生物标志物以及包括CD68在内的几种斑块炎症相关基因的表达水平显著相关。它已被用于多中心试验，以测量抗炎治疗后动脉炎症的变化。在这项辅助的CIRT成像研究中，我们建议使用这一经过充分验证的方法来直接可视化血管炎症。我们将利用现有的基础设施、患者群体和作为CIRT的一部分而建立的专业知识，在参加主要CIRT试验的患者子集中测试LDM对斑块炎症的直接影响，这是通过无创系列FDG-PET/CT评估的。拟议的辅助研究将提供补充信息，以增加从母公司CIRT试验中获得的知识和机械性见解。来自三个大都市(纽约、波士顿和多伦多)的CIRT中心的216名受试者将使用相同的方案和设备进行成像。18-FDG-PET成像数据和炎症生物标志物将被获取、集中分析并将结果纳入主CIRT数据库。我们假设a)随机分组后，与安慰剂相比，LDM治疗将导致斑块炎症显著减少；b)循环全身炎症生物标记物(如hs-CRP)与动脉炎症之间将存在正相关；c)基于成像数据的模型可以准确地识别母研究中最有可能经历心血管事件减少的个体亚组。因此，我们将测试以下特定目标：1)确定FDG-PET/CT成像评估的LDM抗炎治疗对动脉炎症的影响；2)评估成像终点的变化与全身炎症生物标志物变化的关系；3)开发和验证基于LDM分配、基线患者特征和基线血液生物标志物预测成像终点变化的模型；以及评估这些预测变化与CIRT人群中临床结果的关系。

 DESCRIPTION (provided by applicant): Vascular inflammation is a central feature of atherosclerosis and is involved in initiation, perpetuation and instability of plaques. It is uncler if a reduction in vascular inflammation with an intervention that does not alter other causal pathways in the atherosclerotic process can reduce future cardiovascular (CV) events. The NHLBI funded (Ridker 5U01HL101422) Cardiovascular Inflammation Reduction Trial (CIRT) investigates if low dose methotrexate (LDM) can reduce CV morbidity and mortality among patients with a prior myocardial infarction. It is crucial to incorporate a measure of vascular inflammation imaging for confirmation of the primary mechanism of action underlying the CIRT trial. 18-fluoro-deoxy-glucose positron emission tomography/computed tomography (18-FDG-PET/CT) has been established as a reproducible measure of vascular inflammation, shown to correlate significantly and consistently with plaque macrophage content, numerous circulating inflammatory biomarkers and expression levels of several plaque inflammation associated genes, including CD68. It has been employed in multi-center trials to measure changes in arterial inflammation in response to anti-inflammatory treatments. In this ancillary CIRT imaging study, we propose to use this well validated approach to directly visualize vascular inflammation. We will leverage the infrastructure, patient population and expertise available and established as part of CIRT to test the direct effects of LDM on plaque inflammation as assessed by non-invasive serial FDG-PET/CT in a subset of patients enrolled in the main CIRT trial. The proposed ancillary study would provide complementary information that would increase the knowledge and mechanistic insights gained from the parent CIRT trial. 216 subjects from CIRT centers in three metropolitan areas (New York, Boston and Toronto) will be imaged using identical protocols and equipment. 18-FDG-PET imaging data and biomarkers of inflammation will be acquired, analyzed centrally and results incorporated into the main CIRT database. We hypothesize that a) LDM treatment will result in a significant decrease in plaque inflammation as compared to placebo between baseline and 8 months after randomization b) that there will be a positive association between circulating systemic inflammatory biomarkers (such as hs-CRP) and arterial inflammation and c) a model based on imaging data can accurately identify the sub-groups of individuals within the parent study that are most likely to experience a reduction in CVD events. Accordingly, we will test the following Specific Aims 1) determine the impact of anti-inflammatory treatment with LDM on arterial inflammation, as assessed by FDG-PET/CT imaging 2) evaluate changes in imaging endpoints in relation to changes in systemic inflammatory biomarkers and 3) develop and validate models that predict changes in imaging endpoints based on LDM assignment, baseline patient characteristics, and baseline blood biomarkers; and to evaluate the relationships of these predicted changes with clinical outcomes within the CIRT population.