Cardiovascular Inflammation Reduction Trial (CIRT) - Inflammation Imaging Study

 描述（由申请人提供）：血管炎症是动脉粥样硬化的主要特征，并参与斑块的发生、持续和不稳定。如果通过不改变动脉粥样硬化过程中其他因果通路的干预减少血管炎症，是否可以减少未来的心血管（CV）事件，这是不可能的。NHLBI资助的（Ridker 5 U 01 HL 101422）心血管炎症减轻试验（CIRT）研究了低剂量甲氨蝶呤（LDM）是否可以降低既往心肌梗死患者的CV发病率和死亡率。结合血管炎症成像的测量对于确认CIRT试验的主要作用机制至关重要。18-氟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）已被确立为血管炎症的可重复测量，显示与斑块巨噬细胞含量、许多循环炎症生物标志物和几种斑块炎症相关基因（包括CD 68）的表达水平显著且一致相关。它已被用于多中心试验，以测量动脉炎症对抗炎治疗的反应。在这项辅助CIRT成像研究中，我们建议使用这种经过充分验证的方法直接可视化血管炎症。我们将利用现有的基础设施、患者人群和专业知识，并作为CIRT的一部分建立，以测试LDM对斑块炎症的直接影响，通过非侵入性连续FDG-PET/CT在主要CIRT试验入组的患者亚组中进行评估。拟定的辅助研究将提供补充信息，增加从母CIRT试验中获得的知识和机制见解。将使用相同的方案和设备对来自三个大都市地区（纽约、波士顿和多伦多）CIRT中心的216名受试者进行成像。将采集18-FDG-PET成像数据和炎症生物标志物，集中分析，并将结果纳入主要CIRT数据库。我们假设a）LDM治疗将导致基线至随机化后8个月之间斑块炎症与安慰剂相比显著减少B）循环全身炎症生物标志物之间存在正相关性c）基于成像数据的模型可以准确地识别亚急性炎症（如hs-CRP）和动脉炎症，以及母研究中最有可能经历CVD事件减少的个体组。因此，我们将测试以下具体目的：1）确定LDM抗炎治疗对动脉炎症的影响，如通过FDG-PET/CT成像评估的; 2）评价成像终点的变化与全身炎症生物标志物的变化的关系;以及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;并评价CIRT人群中这些预测变化与临床结局的关系。

 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.