What is the clinical evidence from this study?

Study design: Other. Population: Systolic Heart Failure (n=7). Intervention: Anakinra vs. Baseline. Primary outcome: Peak oxygen consumption (VO2) (p=0.016).

March 16, 2012Open Access

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

Key Result

Anakinra treatment for 14 days significantly improved median peak oxygen consumption from 12.3 to 15.1 mL/kg/min in patients with systolic heart failure and elevated inflammatory signaling.

PICO

Population

Systolic Heart Failure (n=7)

Intervention / Comparator

Anakinra vs Baseline (100 mg subcutaneous injection daily)

Primary Outcome

Peak oxygen consumption (VO2), p=0.016

Main Result

Absolute Event Rate: 15.1% vs 12.3%

p-value: p=0.016

Limitations

Inability to elucidate the exact signaling mechanism of IL-1-induced systolic dysfunction
IL-1β is not the only circulating factor in human plasma with the potential to alter cardiac function
Lack of randomization limits the interpretation of study results to imply a definitive cause-and-effect relationship
Small sample size inherent to a pilot study design

Abstract

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-1β (IL-1β) 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-1β-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-1β 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 (VO(2)) 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)/VCO(2) 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-1β activity contributes to poor exercise tolerance in patients with systolic HF and identifies IL-1β blockade as a novel strategy for pharmacologic intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT01300650.

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