Objectives The purpose of this study was to assess the safety and efficacy of recombinant human neuregulin-1 (rhNRG-1) in chronic heart failure (CHF) patients. Background Neuregulin-1 plays important roles in maintaining cardiomyocyte structure and cardiac pumping functionality and physiology. Previously, rhNRG-1 was proven to be effective in treating heart failure in animals by reducing enddiastolic volume (EDV) and end-systolic volume (ESV) and increasing left ventricular ejection fraction (LVEF%). Methods A total of 44 CHF patients designated as New York Heart Association functional class II or III were enrolled in a double-blind, randomized manner and treated with a placebo or rhNRG-1 (0.3, 0.6, or 1.2 mu g/kg/day) for 10 days, in addition to standard therapies. The follow-up period was 90 days; left ventricular function and structure measured by magnetic resonance imaging were the primary end points. Results Although not statistically different from placebo, the LVEF% was significantly increased by 27.11 +/- 31.12% (p = 0.009) at day 30 after rhNRG-1 treatment in the 0.6-mu g/kg group, whereas it was only increased 5.83 +/- 25.75% in the placebo group (p = 0.49). In addition, there were decreases in ESV (-11.58 +/- 12.74%, p = 0.002) and EDV (-5.64 +/- 10.03%, p = 0.05) in the 0.6-mu g/kg/day group at day 30; more importantly, both ESV and EDV levels continued to decrease at day 90 (-20.79 +/- 17.03% and -14.03 +/- 13.17%, respectively), accompanied by a sustained increase in LVEF%. This suggests that short-term treatment with rhNRG-1 results in a long-term reversal of remodeling. The effective dose was proven to be tolerable and safe for CHF patients. Conclusions rhNRG-1 improved the cardiac function of CHF patients by increasing the LVEF% and showed the capability of antire-modeling 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) (J Am Coll Cardiol 2010;55:1907-14) (C) 2010 by the American College of Cardiology Foundation