Enhanced Interleukin-1 Activity Contributes to Exercise Intolerance in Patients with Systolic Heart Failure

Background: Heart failure (HF) is a complex clinical syndrome characterized by impaired cardiac function and poor exercise tolerance. Enhanced inflammation is associated with worsening outcomes in HF patients and may play a direct role in disease progression. Interleukin-1 beta (IL-1 beta) is a pro-inflammatory cytokine that becomes chronically elevated in HF and exerts putative negative inotropic effects. Methods and Results: We developed a model of IL-1 beta-induced left ventricular (LV) dysfunction in healthy mice that exhibited a 32% reduction in LV fractional shortening (P<0.001) and a 76% reduction in isoproterenol response (P<0.01) at 4 hours following a single dose of IL-1 beta 3 mcg/kg. This phenotype was reproducible in mice injected with plasma from HF patients and fully preventable by pretreatment with IL-1 receptor antagonist (anakinra). This led to the design and conduct of a pilot clinical to test the effect of anakinra on cardiopulmonary exercise performance in patients with HF and evidence of elevated inflammatory signaling (n = 7). The median peak oxygen consumption (VO2) improved from 12.3 [10.0, 15.2] to 15.1 [13.7, 19.3] mL.kg(-1).min(-1) (P = 0.016 vs. baseline) and median ventilator efficiency (V-E/VCO2 slope) improved from 28.1 [22.8, 31.7] to 24.9 [22.9, 28.3] (P = 0.031 vs. baseline). Conclusions: These findings suggest that IL-1 beta activity contributes to poor exercise tolerance in patients with systolic HF and identifies IL-1 beta blockade as a novel strategy for pharmacologic intervention.