Abstract 15531: Neuregulin-1β Improves Cardiac Remodeling After MI in Swine
Neuregulin-1β (NRG-1β) is a growth factor that is critical for cardiac development. In the adult heart NRG-1β is a stress-activated mediator of cardiac repair after injury which led to the development of the recombinant NRG-1β Glial Growth Factor-2 (GGF2) as a possible therapy for systolic heart failure. The effects of GGF2 on combined indices of systolic and diastolic function and inotropic reserve are not known. Here, we examined the effect of GGF2 on systolic and diastolic function, and acute and chronic responses to inotropic challenge in a swine myocardial infarction (MI) model.
Materials and Methods: We induced MI by balloon occlusion (60 min) of the left anterior descending artery in male Yorkshire pigs (n=19, mean weight 54.5 kg, age < 1 year). Pigs received either GGF2 or placebo biweekly. The initial dose of 2 mg/kg GGF2 was reduced to 0.67 mg/kg after the first 2 pigs due to side effects of lethargy and vomitting. Cardiac function was measured 1 and 5 weeks post-MI by echocardiography. Terminal hemodynamic assessment was performed at five weeks using a Millar catheter. Acute hemodynamic responses to dobutamine were assessed at baseline and 20 minutes after an acute dose of GGF2.
Results: 11 out of 19 pigs survived the MI. One pig was terminated early (17 days) due to acute illness. Left ventricular ejection fraction (LVEF) was not different in control (n=4) vs. GGF2 (n=6) groups at 7 days post-MI. At 5 weeks treated pigs had higher LVEF (61 ± 12% vs. 32± 4% in controls, p = 0.046) and lower end-diastolic volume (205 ± 5 ml vs. 315 ± 7 in controls, p <0.0001). Baseline maximum and minimum dP/dt were reduced in treated pigs compared to control animals (P= 0.0002), whereas response to dobutamine was similar. There was no acute effect of GGF2 on heart rate, blood pressure, maximum or minimum dP/dt. Pulmonary congestion was reduced in treated pigs as assessed by post-mortem lung wet to dry weight ratio.
Conclusions: GGF2 treatment improved LVEF and remodeling in pigs post-MI. Hemodynamic data show a blunted maximum and minimum dP/dT in treated pigs with preserved inotropic reserve. Further investigation is needed to understand potential mechanisms for the beneficial effects of GGF2 in systolic heart failure.
- © 2011 by American Heart Association, Inc.