Abstract
BACKGROUND: Echocardiographic molecular imaging techniques are beginning to be applied to evaluate preclinical efficacy of new drugs. In a large clinical trial, anti-interleukin-1β (IL-1β) immunotherapy reduced atherosclerotic events, yet treatment effects were modest, and the mechanisms of action were not fully elucidated. We tested the hypothesis that echocardiographic molecular imaging can assess changes in vascular thromboinflammatory status in response to anti-IL-1β therapy. METHODS: In wild-type and atherosclerotic mice deficient for the low-density lipoprotein-receptor and Apobec-1, closed-chest myocardial infarction (MI) was performed to mimic high-risk clinical cohorts. Control animals had sham surgery. Post-MI animals were randomized to either no therapy or anti-IL-1β immunotherapy, which was continued weekly. At post-MI day 3 or 21, in vivo ultrasound molecular imaging of aortic VCAM-1, P-selectin, von Willebrand factor A1-domain, and platelet GPIbα in the thoracic aorta was performed. Aortic histology and NF-κB activity were assessed in atherosclerotic mice. RESULTS: In both atherosclerotic and wild-type mice, MI produced a several-fold increase (P < .05) in aortic molecular signals for P-selectin, VCAM-1, von Willebrand factor, and GPIbα. In atherosclerotic mice, signal remained elevated at day 21. Anti-IL-1β therapy completely abolished the post-MI increase in signal for all endothelial targets (P < .05 vs nontreated) at day 3 and 21. In atherosclerotic mice, MI triggered an increase in aortic plaque growth and macrophage content, a decrease in plaque collagen, and elevated aortic NF-κB (P < .05 for all changes). All of these remote plaque adverse changes were inhibited by anti-IL-1β therapy. CONCLUSIONS: Echocardiographic molecular imaging of the vascular endothelium can quantify the beneficial effects of therapies designed to suppress the proatherosclerotic arterial thromboinflammatory effects of alarmins such as IL-1β. This approach could potentially be used to evaluate the biologic variables that influence response in preclinical studies, and possibly to select patients most likely to benefit from therapy.