Effects of Interleukin-1 Blockade With Anakinra on Adverse Cardiac Remodeling and Heart Failure After Acute Myocardial Infarction [from the Virginia Commonwealth University-Anakinra Remodeling Trial (2) (VCU-ART2) 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 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.

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].…”

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

“…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.…”

“…The aim of this study was to determine the effects of anakinra on the activity of leukocytes measured ex vivo. Therefore, we measured the spontaneous and inducible production ex vivo of IL-6, a key secondary proinflammatory cytokine, in leukocytes obtained from 17 patients with STEMI enrolled in a clinical trial of anakinra or placebo (9). the Virginia Commonwealth UniversityAnakirna Remodeling Trial (2) (VCU-ART2), representing 57% of all patients (9).…”

“…the Virginia Commonwealth UniversityAnakirna Remodeling Trial (2) (VCU-ART2), representing 57% of all patients (9). The VCU-ART2 study enrolled 30 patients with ST-segment elevation acute myocardial infarction, randomized, double-blinded, to anakinra 100 mg daily or placebo for 14 d. The primary endpoint of differences in interval change in left ventricular end-systolic volume index between anakinra and placebo at 3 months was measured with cardiac magnetic resonance, as an expression of adverse remodeling (www.clinicaltrials.gov, NCT01175018) (9).…”

“…Complete WBC count and high-sensitivity CRP levels were also measured at the same time of whole blood cultures, as described (9). Data are expressed as pg/mL but normalized to cytokine per leukocytes.…”