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

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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.