Interleukin-1 Blockade With Anakinra to Prevent Adverse Cardiac Remodeling After Acute Myocardial Infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot Study)

Abstract

Acute myocardial infarction (AMI) initiates an intense inflammatory response in which interleukin-1 (IL-1) plays a central role. The IL-1 receptor antagonist is a naturally occurring antagonist, and anakinra is the recombinant form used to treat inflammatory diseases. The aim of the present pilot study was to test the safety and effects of IL-1 blockade with anakinra on left ventricular (LV) remodeling after AMI. Ten patients with ST-segment elevation AMI were randomized to either anakinra 100 mg/day subcutaneously for 14 days or placebo in a doubleblind fashion. Two cardiac magnetic resonance (CMR) imaging and echocardiographic studies were performed during a 10-to 14-week period. The primary end point was the difference in the interval change in the LV end-systolic volume index (LVESVi) between the 2 groups on CMR imaging. The secondary end points included differences in the interval changes in the LV enddiastolic volume index, and C-reactive protein levels. A +2.0 ml/m 2 median increase (interquartile range +1.0, +11.5) in the LVESVi on CMR imaging was seen in the placebo group and a -3.2 ml/ m 2 median decrease (interquartile range -4.5, -1.6) was seen in the anakinra group (p = 0.033). The median difference was 5.2 ml/m 2 . On echocardiography, the median difference in the LVESVi change was 13.4 ml/m 2 (p = 0.006). Similar differences were observed in the LV enddiastolic volume index on CMR imaging (7.6 ml/m 2 , p = 0.033) and echocardiography (9.4 ml/m 2 , p = 0.008). The change in C-reactive protein levels between admission and 72 hours after admission correlated with the change in the LVESVi (R =+0.71, p = 0.022). In conclusion, in the present pilot study of patients with ST-segment elevation AMI, IL-1 blockade with anakinra was safe and favorably affected by LV remodeling. If confirmed in larger trials, IL-1 blockade might represent a novel therapeutic strategy to prevent heart failure after AMI.Acute myocardial infarction (AMI) initiates an intense inflammatory response characterized by an accumulation of leukocytes in the injured myocardium and the production of cytokines and chemokines, which further promotes adverse cardiac remodeling and heart failure. [1][2][3] Interleukin-1 (IL-1) is the prototypic inflammatory cytokine, inducing adhesion NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript molecules and chemokines. 4 IL-1 is also a known myocardial suppressant. [4][5] In AMI, IL-1 is initially released by the ischemic endothelial cells and cardiomyocytes and, later, by the leukocytes infiltrating the myocardium. 6 Although IL-1 leads to leukocyte recruitment, which contributes to infarct healing, IL-1 also promotes cell death in cardiomyocytes. 6,7 The naturally occurring IL-1 receptor antagonist binds to the IL-1 receptor and prevents IL-1 activity. 4 We have reported that a recombinant human IL-1 receptor antagonist, anakinra, ameliorated cardiac remodeling after a large anterior wall AMI in the experimental mouse model and improved survival. 7 Moreover, mice with...

Genetic variability in the IL1RN gene and the balance between interleukin (IL)-1 receptor agonist and IL-1β in idiopathic pulmonary fibrosis

“…The pathogenetic processes in bleomycin-induced fibrosis are simply a model for IPF and results cannot be extrapolated to human IPF. However, in patients with acute myocardial infarction, there is evidence that IL-1 blockade with IL-1Ra suppresses the inflammatory response and positively affects tissue remodelling [24].…”

Leukocyte Activity in Patients with ST-Segment Elevation Acute Myocardial Infarction Treated with Anakinra

“…We have recently reported that, in patients with STEMI, anakinra significantly blunted the acute systemic response measured as leukocyte count and CRP levels (8,9). Here we describe the effects of anakinra on leukocyte activity.…”

“…However, only recently has IL-1 emerged as a novel target for intervention in heart disease (7). The initial experience with anakinra, the recombinant form of the naturally occurring human IL-1 receptor antagonist, in patients with ST-segment elevation myocardial infarction (STEMI) suggests that IL-1 blockade blunts the acute systemic inflammatory response, since leukocyte counts and plasma C-reactive protein (CRP) levels were reduced, as well as the incidence of heart failure (8,9). Yet, the effects of anakinra on leukocyte activity in patients with STEMI remain unknown.…”

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

“…Small-scale clinical trials have also sought to evaluate the effect of IL-1 inhibition on inflammation and cardiac remodelling in stable-STEMI and non-STEMI patients [155,156], reporting that IL-1 inhibition reduced post-MI inflammation but had little effect on cardiac function in the longer term. This may relate to the relatively mild inflammatory phenotype in these patient cohorts compared with less stable STEMI patients, in which IL-1 blockade was more effective [157]. Further studies in patients with more severe MI are likely to be required to evaluate the true potential of IL-1 inhibition as an effective therapy for post-MI morbidity and mortality.…”