Differential response to interleukin-1 blockade with anakinra on cardiorespiratory fitness in patients with heart failure with preserved ejection fraction stratified according to ejection fraction

Abstract

Abstract Background Patients with heart failure with preserved ejection fraction (HFpEF) are a heterogeneous clinical population and might respond differently to pharmacologic therapies based on their baseline left ventricular EF (LVEF) (50-59% vs. ≥60%). Interleukin-1 (IL-1) is a key pro-inflammatory cytokine being explored as a therapeutic target in HFpEF for its effects on numerous outcomes including cardiorespiratory fitness (CRF). Purpose Our aim was to examine changes in CRF and C-reactive protein (CRP), a surrogate for IL-1 activity, in patients with HFpEF treated with the IL-1 recombinant human receptor antagonist anakinra, stratified according to resting LVEF. Methods We analyzed data from 32 patients (median age 55 [51-64] years, 24 (75%) female) with HFpEF, defined as a presence of HF symptoms, LVEF≥50%, and evidence of left ventricular diastolic dysfunction or elevated filling pressures. All patients were treated with anakinra 100 mg subcutaneously daily for 12 [2-12] weeks. Patients were stratified into two groups: LVEF 50-59% and LVEF ≥60%. At baseline and during treatment, patients underwent cardiopulmonary exercise testing and venipuncture to measure changes in peak oxygen consumption (peak VO2) and CRP. Categorical and continuous variables are expressed as N (%) and median (interquartile range) and were compared with the chi-square and Mann-Whitney test, respectively. The within-group paired differences were compared using the Wilcoxon signed-rank test. Results The cohort included 15 patients with LVEF 50-59% and 17 with LVEF ≥60%, without significant differences in age and sex between groups. In patients with LVEF 50-59% and ≥60%, baseline peak VO2 was 14.1 [13.1–17.3] and 13.8 [11.8-18.6] mLO2·kg-1·min-1, respectively (p = 0.82), and CRP was 6.2 [3.4-15.9] and 6.1 [3.7-17.6] mg/L, respectively (p = 0.74). A significant increase in peak VO2 (from 13.8 [11.8-18.6] to 15.8 [12.7-19.9] mLO2·kg-1·min-1, p = 0.033) and decrease in CRP (from 6.2 [3.4-15.9] mg/L to 3.4 [1.0-6.7] mg/L, p = 0.003) was seen in patients with LVEF ≥60%; whereas in those with LVEF 50-59% there were no significant changes in peak VO2 (from 14.1 [13.1–17.3] to 14.1 [11.0–17.3] mLO2·kg-1·min-1, p = 0.25) despite a significant reduction in CRP (from 6.1 [3.7-17.6] mg/L to 1.4 [0.8-11.4] mg/L, p = 0.016). We found a difference in the interval changes in peak VO2 (0 [from -1.1 to +0.3] vs +1.7 [from -0.7 to +2.3] mLO2·kg-1·min-1 in patients with LVEF 50-59% and ≥60%, respectively, p = 0.01), without differences in the interval change in CRP levels (–3.5 [from -6 to -2.1] vs –3.0 [from -11.4 to -2.1] mg/L, respectively, p = 0.91). Figure 1. Conclusions Patients with HFpEF demonstrate differential peak VO2 response to anakinra treatment based on resting LVEF, with those with a LVEF ≥60% showing greater improvement in CRF. Further randomized control trials are needed to validate these data and explore the potential underlying mechanisms.