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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 (beta2a isoform; rhNRG-1) in patients with stable chronic heart failure (CHF).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.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.The trial was registered with the Australian New Zealand Clinical Trials Registry, anzctr.org.au Identifier: ACTRN12607000330448.