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.

Background ST ‐segment–elevation myocardial infarction is associated with an intense acute inflammatory response and risk of heart failure. We tested whether interleukin‐1 blockade with anakinra significantly reduced the area under the curve for hsCRP (high sensitivity C‐reactive protein) levels during the first 14 days in patients with ST ‐segment–elevation myocardial infarction (VCUART3 [Virginia Commonwealth University Anakinra Remodeling Trial 3]). Methods and Results We conducted a randomized, placebo‐controlled, double‐blind, clinical trial in 99 patients with ST ‐segment–elevation myocardial infarction in which patients were assigned to 2 weeks treatment with anakinra once daily (N=33), anakinra twice daily (N=31), or placebo (N=35). hsCRP area under the curve was significantly lower in patients receiving anakinra versus placebo (median, 67 [interquartile range, 39–120] versus 214 [interquartile range, 131–394] mg·day/L; P <0.001), without significant differences between the anakinra arms. No significant differences were found between anakinra and placebo groups in the interval changes in left ventricular end‐systolic volume (median, 1.4 [interquartile range, −9.8 to 9.8] versus −3.9 [interquartile range, −15.4 to 1.4] mL; P =0.21) or left ventricular ejection fraction (median, 3.9% [interquartile range, −1.6% to 10.2%] versus 2.7% [interquartile range, −1.8% to 9.3%]; P =0.61) at 12 months. The incidence of death or new‐onset heart failure or of death and hospitalization for heart failure was significantly lower with anakinra versus placebo (9.4% versus 25.7% [ P =0.046] and 0% versus 11.4% [ P =0.011], respectively), without difference between the anakinra arms. The incidence of serious infection was not different between anakinra and placebo groups (14% versus 14%; P =0.98). Injection site reactions occurred more frequently in patients receiving anakinra (22%) versus placebo (3%; P =0.016). Conclusions In patients presenting with ST ‐segment–elevation myocardial infarction, interleukin‐1 blockade with anakinra significantly reduces the systemic inflammatory response compared with placebo. Clinical Trial Registration URL : https://www.clinicaltrials.gov/ . Unique identifier: NCT 01950299.

BACKGROUND: Enhanced inflammation may lead to exercise intolerance in heart failure with preserved ejection fraction. The aim of the current study was to determine whether IL (interleukin)-l blockade with anakinra improved cardiorespiratory fitness in heart failure with preserved ejection fraction. METHODS AND RESULTS: Thirty-one patients with heart failure with preserved ejection fraction and CRP (C-reactive protein) >2 mg/L were randomized to anakinra (100 mg subcutaneously daily, N=21) or placebo (N=10) for 12 weeks. We measured peak oxygen consumption (Vo2), ventilatory efficiency (VE/Vco2 slope), and high-sensitivity CRP and NT-proBNP (N-terminal pro-B-type natriuretic peptide) at 4, 12, and 24 weeks. Twenty-eight patients completed ≥2 visits, 18 women (64%), 27 (96%) obese. There were no differences in peak Vo2 or VE/Vco2 slope between groups at baseline. Peak Vo2 was not changed after 12 weeks of anakinra (from 13.6 [11.8–18.0] to 14.2 [11.2–18.5] mL-kg−1-min−1, P=0.89), or placebo (14.9 [11.7–17.2] to 15.0 [13.8–16.9] mL-kg−1-min−1, P=0.40), without significant between-group differences in changes at 12 weeks (−0.4 [95% CI, −2.2 to +1.4], P=0.64). VE/Vco2 slope was also unchanged with anakinra (from 28.3 [27.2–33.0] to 30.5 [26.3–32.8], P=0.97) or placebo (from 31.6 [27.3–36.9] to 31.2 [27.8–33.4], P=0.78), without significant between-group differences in changes at 12 weeks (+1.2 [95% CI, −1.8 to +4.3], P=0.97). Within the anakinra-treated patients, high-sensitivity CRP and NT-proBNP levels were lower at 4 weeks compared with baseline (P=0.026 and P=0.022 versus placebo [between-group analysis], respectively). CONCLUSIONS: Treatment with anakinra for 12 weeks failed to improve peak Vo2 and VE/Vco2 slope in a group of obese heart failure with preserved ejection fraction patients. The favorable trends in high-sensitivity CRP and NT-proBNP with anakinra deserve exploration in future studies. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: .