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.
Inflammation is a prominent feature of atherosclerotic plaques at high risk for causing cardiovascular events. By proposing a sub-study of the NHLBI funded (Ridker 5U01HL101422) Cardiovascular Inflammation Reduction Trial (CIRT), we aim to use 18F FDG PET/CT imaging to investigate if the administration of low dose methotrexate can reduce vascular inflammation. The proposed ancillary study would provide unique and highly complementary information that would greatly increase the knowledge and mechanistic insights gained from the parent CIRT trial.
| Fayad, Zahi A; Swirski, Filip K; Calcagno, Claudia et al. (2018) Monocyte and Macrophage Dynamics in the Cardiovascular System: JACC Macrophage in CVD Series (Part 3). J Am Coll Cardiol 72:2198-2212 |
| Dweck, Marc R; Fayad, Zahi A (2017) Multitarget Vulnerable Plaque Imaging. Circ Cardiovasc Imaging 10: |
| Zupan?i?, Eva; Fayad, Zahi A; Mulder, Willem J M (2017) Cardiovascular Immunotherapy and the Role of Imaging. Arterioscler Thromb Vasc Biol 37:e167-e171 |
| Alaarg, Amr; Pérez-Medina, Carlos; Metselaar, Josbert M et al. (2017) Applying nanomedicine in maladaptive inflammation and angiogenesis. Adv Drug Deliv Rev 119:143-158 |
| Dweck, Marc R; Williams, Michelle C; Moss, Alastair J et al. (2016) Computed Tomography and Cardiac Magnetic Resonance in Ischemic Heart Disease. J Am Coll Cardiol 68:2201-2216 |
