Background: Regenerative strategies have the potential to transform heart failure therapies. Cell transplantation strategies have shown effectiveness and safety in clinical trials. A complementary strategy is based on directly stimulating the proliferation of endogenous cardiomyocytes. We have demonstrated that administration of the growth factor neuregulin (rNRG1), which has passed phase 2 testing, stimulates cardiomyocyte proliferation and improves myocardial repair in adult animal models. Since cardiomyocyte proliferation is active during myocardial growth, we hypothesized that NRG1 may be more effective in growing animals and humans.
Methods: We developed a myocardial injury model (cryoinjury) in neonatal mice that recapitulates scar formation seen in infants with congenital heart disease (CHD). In contrast with ligation of the left anterior descending coronary artery (LAD), cryoinjury reduced cardiomyocyte cell cycle activity. We used this model to evaluate the effectiveness of rNRG1 administration. To assess the ability of rNRG1 to stimulate human cardiomyocyte proliferation, we developed an organotypic culture system for myocardium from infants with CHD.
Results: Administration of NRG1 resulted in a 2-fold increase in cardiomyocyte cell cycle activity at 10 days post injury (dpi). After neonatal cryoinjury in mice, administration of rNRG1 from birth to 30 days of life significantly improved the ejection fraction, which was sustained for 30 days after the cessation of rNRG1 administration. In contrast, administration of NRG1 four to 34 days after cryoinjury transiently reduced scar formation, and transiently improved myocardial structure and function. In myocardium from infants with Tetralogy of Fallot (ToF) less than 6 months of age (n = 6), rNRG1 induced cardiomyocyte proliferation.
Conclusions: These results indicate that stimulating cardiomyocyte proliferation may be clinically effective in human infants with heart disease, a population in whom a significant and unmet need exists.