Abstract 18952: A Novel Engineered Neuregulin-hydrogel System Regenerates Mammalian Heart Muscle and Enhances Ventricular Function in a Preclinical Ovine Model of Ischemic Cardiomyopathy
Objective: The clinical efficacy of neuregulin (NRG), a ligand of the Her family receptors, is hindered by off-target exposure and requisite daily systemic infusions. We recently encapsulated NRG in a hydrogel (HG) for targeted and sustained myocardial delivery; beneficial results in a murine model of ischemic cardiomyopathy were clear. Here, we evaluate NRG-HG’s translational potential for myocardial regeneration and functional improvement in the clinical realm using a preclinical ovine model of ischemic cardiomyopathy.
Methods: Male Dorset sheep (n=30) underwent baseline cardiac assessment with MRI and pressure-volume (PV) catheterization. Myocardial infarction (MI) was induced by ligating the 2nd and 3rd diagonal artery branches, and sheep were randomized to receive myocardial borderzone injection of 1mL saline, HG alone, NRG alone, or NRG-HG. Eight weeks post-infarction, repeat hemodynamic assessment was performed followed by tissue acquisition. A subset underwent sacrifice at 1 week for molecular analyses.
Results: Analysis of myocardial borderzone 1-week post-infarction revealed NRG-HG augmented phosphorylated ErbB4, ErbB2, ERK, and histone h3 compared with all other groups. This marker activation suggests receptor activation, downstream signaling, and cardiac cell-cycle entry. At 8 weeks, NRG-HG significantly reduced scar size and augmented ventricular function (Table). There was no evidence of off-target NRG at 1 and 8 weeks, and no evidence of gel embolization or neurologic insult (by brain MRI) from intramyocardial hydrogel delivery.
Conclusion: Targeted and sustained intramyocardial delivery of NRG with an engineered hydrogel platform triggers regeneration of mammalian heart muscle and augments ventricular function in a large animal model of ischemic cardiomyopathy. This novel, engineered delivery system realizes the true potential of NRG and its translation to clinical regenerative therapeutics.
Author Disclosures: J.E. Cohen: None. A.B. Goldstone: None. B.P. Purcell: None. Y. Shudo: None. J.W. MacArthur, Jr.: None. B.B. Edwards: None. J.B. Patel: None. M.S. Hopkins: None. A. Eskandari: None. A.N. Steele: None. N.C. Cheung: None. C.N. Aribeana: None. J.A. Burdick: None. Y. Woo: None.
- © 2015 by American Heart Association, Inc.