These beneficial effects make rhNRG-1 promising as a broad-spectrum therapeutic for the treatment of heart failure due to a variety of common cardiac diseases.

rhNRG-1 improved the cardiac function of CHF patients by increasing the LVEF% and showed the capability of antiremodeling by decreasing ESV and EDV compared with pre-treatment. (A Randomized, Double-Blind, Multi-Center, Placebo Parallel controlled, Standard Therapy Based Phase II Clinical Trial to Evaluate the Efficacy and Safety of Recombinant Human Neuregulin-1 for Injection in Patients with Chronic Heart Failure; ChiCTR-TRC-00000414).

AimsNeuregulin-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). Methods and resultsFifteen 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. ConclusionrhNRG-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 InformationThe trial was registered with the Australian New Zealand Clinical Trials

Rationale:The cardiac gene regulatory network (GRN) is controlled by transcription factors and signaling inputs, but network logic in development and it unraveling in disease is poorly understood. In development, the membrane-tethered signaling ligand Neuregulin (Nrg)1, expressed in endocardium, is essential for ventricular morphogenesis. In adults, Nrg1 protects against heart failure and can induce cardiomyocytes to divide.Objective: To understand the role of Nrg1 in heart development through analysis of null and hypomorphic Nrg1 mutant mice. Methods and Results:Chamber domains were correctly specified in Nrg1 mutants, although chamber-restricted genes Hand1 and Cited1 failed to be activated. The chamber GRN subsequently decayed with individual genes exhibiting decay patterns unrelated to known patterning boundaries. Both trabecular and nontrabecular myocardium were affected. Network demise was spatiotemporally dynamic, the most sensitive region being the central part of the left ventricle, in which the GRN underwent complete collapse. Other regions were partially affected with graded sensitivity. In vitro, Nrg1 promoted phospho-Erk1/2-dependent transcription factor expression, cardiomyocyte maturation and cell cycle inhibition. We monitored cardiac pErk1/2 in embryos and found that expression was Nrg1-dependent and levels correlated with cardiac GRN sensitivity in mutants. Conclusions:The chamber GRN is fundamentally labile and dependent on signaling from extracardiac sources.Nrg1-ErbB1/4 -Erk1/2 signaling critically sustains elements of the GRN in trabecular and nontrabecular myocardium, challenging our understanding of Nrg1 function. Transcriptional decay patterns induced by reduced Nrg1 suggest a novel mechanism for cardiac transcriptional regulation and dysfunction in disease, potentially linking biomechanical feedback to molecular pathways for growth and differentiation. (Circ Res. 2010;107:715-727.) Key Words: neuregulin 1 Ⅲ cardiac gene regulation Ⅲ heart development Ⅲ cardiac gene regulatory network A n early patterning event in vertebrate heart development is the specification of myocardium of the atrial and ventricular chambers, a specialized muscle adapted to pumping blood through a closed circulatory system at high pressure. 1 Luminal myocytes of the cardiac chambers develop sponge-like convolutions termed trabeculae, which in development serve as a morphological marker for chamber specification. The trabecular zone is also marked by a unique set of genes. Chamber muscle is an electric syncytium through which action potentials spread via gap junctions, guided by caudal pacemaker myocytes and their conduction and Purkinje fiber tracts.Nontrabecular myocardium of the atrium, inner curvature, atrioventricular (AV) canal and outflow tract (OFT) is less specialized for contraction and gives rise to the myogenic layers of the outflow and inflow vessels, and cells of the proximal conduction system including the sinoatrial (SA) and AV nodes. 1 Nontrabecular myocardium also plays a critical role in induct...