Research ArticlePEDIATRIC CARDIOLOGY

Neuregulin stimulation of cardiomyocyte regeneration in mice and human myocardium reveals a therapeutic window

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Science Translational Medicine  01 Apr 2015:
Vol. 7, Issue 281, pp. 281ra45
DOI: 10.1126/scitranslmed.aaa5171

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Young at heart: Restoring cardiac function in children

When children are given adult roles in TV commercials, the results range from adorable to brilliant to simply hilarious. But when children with heart disease were given adult medicines in clinical trials, the results were disappointing—and the need for pediatric-specific treatment regimens became clear. In adult mice, the recombinant growth factor neuregulin-1 (rNRG1) stimulates heart regeneration by driving the proliferation of heart muscle cells (cardiomyocytes). Because young mice bear more proliferation-competent cardiomyocytes than do adult animals, Polizzotti et al. asked whether rNRG1 might put cardiomyocyte proliferation into overdrive if given to mice during the neonatal period. To test their hypothesis, the authors treated newborn mice with rNRG1 at various times after heart injury and found that early treatment starting at 1 day of age boosted cardiomyocyte cell division and heart function in a persistent manner relative to treatment regimens that began at 4 days after birth. rNRG1 also drove cardiomyocyte proliferation in heart muscle isolated from human infants with heart disease who were less than 6 months of age, but not in tissue from older pediatric patients. These findings suggest that rNRG1 administration during the neonatal period might be a new therapeutic strategy for pediatric heart disease. Now that would be brilliant.

Abstract

Therapies developed for adult patients with heart failure have been shown to be ineffective in pediatric clinical trials, leading to the recognition that new pediatric-specific therapies for heart failure must be developed. Administration of the recombinant growth factor neuregulin-1 (rNRG1) stimulates regeneration of heart muscle cells (cardiomyocytes) in adult mice. Because proliferation-competent cardiomyocytes are more abundant in growing mammals, we hypothesized that administration of rNRG1 during the neonatal period might be more effective than in adulthood. If so, neonatal rNRG1 delivery could be a new therapeutic strategy for treating heart failure in pediatric patients. To evaluate the effectiveness of rNRG1 administration in cardiac regeneration, newborn mice were subjected to cryoinjury, which induced myocardial dysfunction and scar formation and decreased cardiomyocyte cell cycle activity. Early administration of rNRG1 to mice from birth to 34 days of age improved myocardial function and reduced the prevalence of transmural scars. In contrast, administration of rNRG1 from 4 to 34 days of age only transiently improved myocardial function. The mechanisms of early administration involved cardiomyocyte protection (38%) and proliferation (62%). We also assessed the ability of rNRG1 to stimulate cardiomyocyte proliferation in intact cultured myocardium from pediatric patients. rNRG1 induced cardiomyocyte proliferation in myocardium from infants with heart disease who were less than 6 months of age. Our results identify an effective time period within which to execute rNRG1 clinical trials in pediatric patients for the stimulation of cardiomyocyte regeneration.

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