Neonatal Heart Regeneration: Comprehensive Literature Review

Background: The adult mammalian heart is incapable of meaningful functional recovery after injury, and thus promoting heart regeneration is 1 of the most important therapeutic targets in cardiovascular medicine. In contrast to the adult mammalian heart, the neonatal mammalian heart is capable of regeneration after various types of injury. Since the first report in 2011, a number of groups have reported their findings on neonatal heart regeneration. The current review provides a comprehensive analysis of heart regeneration studies in neonatal mammals conducted to date, outlines lessons learned, and poses unanswered questions.

Methods: We performed a PubMed search using the keywords "neonatal" and "heart" and "regeneration." In addition, we assessed all publications that cited the first neonatal heart regeneration reports: Porrello et al, Science, Feb 2011 for apical resection injury; Porrello et al, PNAS, Dec 2012 for coronary ligation injury; and Mahmoud et al, Nature Methods, Jan 2014 for surgical methodology. Publications were examined for surgical models used, timing of surgery, and postinjury assessment including anatomic, histological, and functional assessment, as well as conclusions drawn.

Results: We found 30 publications that performed neonatal apical resection, 19 publications that performed neonatal myocardial infarction by coronary artery ligation, and 6 publications that performed cryoinjury using liquid nitrogen-cooled metal probes. Both apical resection and ischemic infarction injury in neonatal mice result in a robust regenerative response, mediated by cardiomyocyte proliferation. On the other hand, several reports have demonstrated that cryoinjury is associated with incomplete heart regeneration in neonatal mice. Not surprisingly, several studies suggest that injury size, as well as surgical and histological techniques, can strongly influence the observed regenerative response and final conclusions. Studies have utilized these neonatal cardiac injury models to identify factors that either inhibit or stimulate heart regeneration.

Conclusions: Overall, there is consensus that both apical resection and coronary ligation injuries during the first 2 days of life result in heart regeneration in neonatal mammals, whereas cryoinjury was not associated with a similar regenerative response. This regenerative response is mediated by proliferation of preexisting cardiomyocytes, and is modifiable by injury size and surgical technique, as well as metabolic, immunologic, genetic, and environmental factors.