title: Enhanced interleukin-1 activity contributes to exercise intolerance in patients with systolic heart failure.
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.
  
  
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01300650.
authors.affiliation: School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, United States of America. bvantassell@vcu.edu
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Van Tassell
authors.forename: Ross A
authors.initials: RA
authors.lastname: Arena
authors.forename: Stefano
authors.initials: S
authors.lastname: Toldo
authors.forename: Eleonora
authors.initials: E
authors.lastname: Mezzaroma
authors.forename: Tania
authors.initials: T
authors.lastname: Azam
authors.forename: Ignacio M
authors.initials: IM
authors.lastname: Seropian
authors.forename: Keyur
authors.initials: K
authors.lastname: Shah
authors.forename: Justin
authors.initials: J
authors.lastname: Canada
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005080:Exercise Test; D017079:Exercise Tolerance / Q000187:drug effects / Q000502:physiology*; D005260:Female; D054143:Heart Failure, Systolic / Q000188:drug therapy / Q000503:physiopathology*; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects; D011994:Recombinant Proteins / Q000008:administration & dosage; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D011994:Recombinant Proteins; D002097:C-Reactive Protein