Parenteral administration of recombinant human neuregulin-1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses.
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.
Jabbour
Andrew
A
Cardiology Department, St Vincent's Hospital, Darlinghurst, 2010 NSW, Australia.
Hayward
Christopher S
CS
Keogh
Anne M
AM
Kotlyar
Eugene
E
McCrohon
Jane A
JA
England
John F
JF
Amor
Raul
R
Liu
Xifu
X
Li
Xin Yan
XY
Zhou
Ming Dong
MD
Graham
Robert M
RM
Macdonald
Peter S
PS
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
D015415:Biomarkers; D020890:Neuregulin-1; D011994:Recombinant Proteins