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 double-blind 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 end-diastolic volume index, and C-reactive protein levels. A +2.0 ml/m2 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/m2 median decrease (interquartile range –4.5, –1.6) was seen in the anakinra group (p = 0.033). The median difference was 5.2 ml/m2. On echocardiography, the median difference in the LVESVi change was 13.4 ml/m2 (p = 0.006). Similar differences were observed in the LV end-diastolic volume index on CMR imaging (7.6 ml/m2, p = 0.033) and echocardiography (9.4 ml/m2, 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.

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome of exercise intolerance due to impaired myocardial relaxation and/or increased stiffness. Patient with HFpEF often show signs of chronic systemic inflammation and experimental studies show that interleukin-1 (IL-1), a key pro-inflammatory cytokine, impairs myocardial relaxation. The aim of the current study was to determine the effects of IL-1 blockade with anakinra on aerobic exercise capacity in patients with HFpEF and plasma C-reactive protein (CRP) >2 mg/l (reflecting increased IL-1 activity). Twelve patients were enrolled in a double-blind, randomized, placebo-controlled, cross-over trial and assigned 1:1 to receive one of the 2 treatments (anakinra 100 mg or placebo) for 14 days and then an additional 14 days of the alternate treatment (placebo or anakinra). Cardiopulmonary exercise testing (CPX) was performed at baseline, after the first 14 days and after the second 14 days. Placebo-corrected interval change in peak oxygen consumption (VO2) was chosen as primary endpoint. All 12 patients enrolled in the study and receiving treatment completed both phases, and experienced no major adverse events. Anakinra led to a statistically significant improvement in peak VO2 (+1.2 ml•kg−1•min−1, P=0.009), and a significant reduction in plasma CRP levels (−74%, P=0.006). The reduction in CRP levels was correlated with the improvement in peak VO2 (R=-0.60, P=0.002). Three patients (25%) had mild and self-limiting injection site reactions. In conclusion, IL-1 blockade with anakinra for 14 days significantly quenches the systemic inflammatory response and improves aerobic exercise capacity in patients with HFpEF and elevated plasma CRP levels.

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Anakinra, the recombinant form of the human interleukin (IL)-1 receptor antagonist, blunts the acute systemic inflammatory response in patients with ST-segment elevation myocardial infarction (STEMI), by determining a fall in peripheral blood leukocyte and plasma C-reactive protein levels. The aim of the present study was to determine the effects of anakinra on the activity of leukocytes measured ex vivo. Blood was collected 72 h after admission in 17 patients enrolled in the Virginia Commonwealth University -Anakirna Remodeling Trial (2) (VCU-ART2) and randomly treated with anakinra (N = 7) or placebo (N = 10). Whole blood was cultured at 37°C for 24 h to measure spontaneous production of IL-6 or stimulated with Escherichia coli lipopolysaccharide (LPS) for toll-like receptor (TLR)-4 or heat-killed Staphylococcus epidermidis (SE) for TLR-2 activation. The cultures of anakinra-treated patients produced significantly less IL-6 spontaneously (71 pg/mL [27-114]) compared with placebo-treated patients (290 pg/mL [211-617], p = 0.005). LPS-or SE-induced IL-6 production, on the other hand, was not statistically different between anakinra-versus placebo-treated patients (344 pg/mL versus 370 pg/mL , p = 0.32 for LPS, and 484 pg/mL versus 615 pg/mL , p = 0.31 for SE, respectively). IL-1 blockade with anakinra in STEMI patients results in reduced spontaneous leukocyte activity ex vivo without impairing the responsiveness to bacterial stimuli.