Abstract 3708: The Safety and Efficacy of Recombinant Human Neuregulin-1 in Patients With Stable Chronic Heart Failure
Background: Neuregulin-1 plays a critical role in the adaptation of the heart to injury, inhibiting apoptosis via ErbB2/ErbB4 receptor stimulation. We have shown previously that rhNRG-1, a 61-amino acid receptor-active recombinant human neuregulin-1 (beta2a isoform) peptide improves cardiac function and survival in various animal models of ischaemic, dilated and viral cardiomyopathy. Here we report the first human study exploring the safety and efficacy of rhNRG-1 in patients with stable chronic heart failure (CHF).
Methods: Fifteen patients (Age, 60±2; NYHA II:III, 9:6; Left Ventricular Ejection Fraction (LVEF) <40%) on optimal medical CHF therapy, received a rhNRG-1 infusion daily for 11 days. Acute and chronic haemodynamic, structural and biochemical effects were measured by serial (days 0, 12, 30, 84) right heart catheterization (RHC), cardiac magnetic resonance (CMR), echocardiography (ECHO) and blood investigations. The primary endpoint was change in LVEF by CMR at 3 months.
Results: Swan Ganz determined cardiac output (CO) increased by 23% during the 6hr rhNRG-1 infusion (4.2±0.2 L/min to 5.5±0.3 L/min; (Mean±SEM) p<0.001) and returned to baseline at 24 hrs. Wedge pressure (PAWP) and systemic vascular resistance decreased (30%, 20% respectively, p<0.001), and stroke volume increased (16%, p<0.001) during the infusion. These acute hemodynamic improvements were associated with a 47% reduction in serum noradrenaline, a 55% reduction in serum aldosterone and direct stimulation of NT-proBNP release, which increased 355% (p<0.001, all measures). LVEF (by CMR) increased from day 12 and remained elevated at 1 and 3 months (32.2±2.0% (baseline) to 36.1±2.3% (3 months); p<0.001). Stroke volume increased by 10.9% (p<0.01) driven by a reduction in LV end systolic volume (9.0%; p=0.01), with no change in LV end diastolic volume. This correlated well with ECHO determined LVEF and improved hemodynamics (blood pressure, PAWP, CO) at 3 months. The therapy was safely administered and well tolerated.
Conclusion: RhNRG-1, via a novel mechanism, produces sustained improvement in cardiac function in patients with stable CHF on optimal medical therapy.