title: Parenteral administration of recombinant human neuregulin-1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses.
abstract: OBJECTIVE
  Neuregulin-1 (NRG-1) plays a critical role in the adaptation of the heart to injury, inhibiting apoptosis and inducing cardiomyocyte proliferation. We have shown previously that rhNRG-1 improves cardiac function and survival in animal models of cardiomyopathy. Here we report the first human study aimed at exploring the acute and chronic haemodynamic responses to recombinant human NRG-1 (beta(2a) isoform; rhNRG-1) in patients with stable chronic heart failure (CHF).
  
  
  RESULTS
  Fifteen patients (age, 60 ± 2; NYHA II:III, 9:6; left ventricular ejection fraction (LVEF) <40%) on optimal medical therapy for CHF, received a rhNRG-1 infusion daily for 11 days. Acute and chronic haemodynamic, structural and biochemical effects were determined by serial right heart catheterization, cardiac magnetic resonance (CMR), echocardiography and measurement of neurohumoral indices. Acutely, cardiac output increased by 30% during a 6 h rhNRG-1 infusion (P < 0.01). Pulmonary artery wedge pressure and systemic vascular resistance decreased 30 and 20%, respectively, at 2 h (P < 0.01). A 47% reduction in serum noradrenaline, a 55% reduction in serum aldosterone and a 3.6-fold increase in N-terminal prohormone brain natriuretic peptide levels were concurrently observed (P < 0.001). These acute haemodynamic effects were sustained, as demonstrated by the 12% increase in LVEF from 32.2 ± 2.0% (baseline) to 36.1 ± 2.3% (mean ± SE, P < 0.001) at 12 weeks. The therapy was well tolerated.
  
  
  CONCLUSIONS
  rhNRG-1 appears to produce favourable acute and chronic haemodynamic effects in patients with stable CHF on optimal medical therapy. Randomized controlled trials of rhNRG-1 in cardiac disease are thus warranted. Clinical Trial Registration Information The trial was registered with the Australian New Zealand Clinical Trials Registry, anzctr.org.au Identifier: ACTRN12607000330448.
authors.affiliation: Cardiology Department, St Vincent's Hospital, Darlinghurst, 2010 NSW, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Jabbour
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Hayward
authors.forename: Anne M
authors.initials: AM
authors.lastname: Keogh
authors.forename: Eugene
authors.initials: E
authors.lastname: Kotlyar
authors.forename: Jane A
authors.initials: JA
authors.lastname: McCrohon
authors.forename: John F
authors.initials: JF
authors.lastname: England
authors.forename: Raul
authors.initials: R
authors.lastname: Amor
authors.forename: Xifu
authors.initials: X
authors.lastname: Liu
authors.forename: Xin Yan
authors.initials: XY
authors.lastname: Li
authors.forename: Ming Dong
authors.initials: MD
authors.lastname: Zhou
authors.forename: Robert M
authors.initials: RM
authors.lastname: Graham
authors.forename: Peter S
authors.initials: PS
authors.lastname: Macdonald
mesh_terms: D000208:Acute Disease; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood; D002908:Chronic Disease; D018450:Disease Progression; D005260:Female; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000097:blood; D007263:Infusions, Parenteral; D008297:Male; D008875:Middle Aged; D020890:Neuregulin-1 / Q000008:administration & dosage* / Q000627:therapeutic use; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000627:therapeutic use; D013318:Stroke Volume / Q000187:drug effects; D016896:Treatment Outcome; D014463:Ultrasonography; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D015415:Biomarkers; D020890:Neuregulin-1; D011994:Recombinant Proteins