Neonatal Heart Regeneration: Mounting Support and Need for Technical Standards

R egenerating the adult heart is by many standards the holy grail of modern cardiovascular medicine. As a result, this field has been fraught with innumerable conflicts and controversies. Everything from the rate of cardiomyocyte turnover and regulators of cardiomyocyte proliferation in the adult heart, to the existence of cardiac progenitors and their therapeutic role, has been heavily contested. In 2011, we published a report outlining the regenerative potential of the neonatal mouse heart in the first few days of life. We found that the newborn mouse heart is capable of regeneration following apical resection of 15% of the left ventricle with only minimal scarring seen in a small percentage of samples. Moreover, we showed that this process is mediated primarily by proliferation of preexisting cardiomyocytes. These studies were inspired by the well-known ability of early neonatal myocytes to divide, even in culture. Our findings have been widely reproduced in mice and rats, and for the first time provided tools and insights for studying regulators of mammalian heart regeneration, whereby loss of regenerative potential of the neonatal heart or prolongation of the postnatal regenerative window can be studied in the context of cardiomyocyte cell cycle regulation. The current report by Konfino and colleagues elegantly compared 2 different forms of neonatal heart injury (namely, apical resection and left anterior descending coronary artery (LAD) ligation), which we first reported in 2011 and 2012, respectively. The results confirmed our previous findings that apical resection is associated with a robust regenerative response and induction of cardiomyocyte proliferation above the basal levels seen in the neonatal heart. However, the current report observed significantly larger scar formation following LAD ligation compared to our findings, associated with lack of induction of cardiomyocyte proliferation. In the 17th century, Robert Boyle argued that reporting scientific methodology is critical for ensuring reproducibility of experimental results. The technical difficulty of performing neonatal heart injury is likely an important reason why these studies have not been attempted prior to our initial report. Technical considerations such as neonatal anesthesia, survival after thoracotomy in the absence of mechanical ventilation, exsanguination after apical resection, and maternal cannibalization are all significant obstacles that can hinder successful neonatal cardiac injury. As a result, we set out to disseminate this surgical technique by training over 30 laboratories, sharing our protocols with numerous others, and publishing a dedicated protocols report. Importantly, many labs with surgical expertise independently established this model following our reports. These efforts undoubtedly helped with standardization and reproducibility of the surgical techniques. Nevertheless, several important technical considerations remain unclear. For example, based on a recent report by the Lee group, it is clear that there is a limit to the degree of neonatal heart regeneration where larger injuries are associated with a higher incidence of incomplete regeneration. Similarly, in the current report by the Leor group, they observed complete regeneration following apical resection, but incomplete regeneration following myocardial infarction. In our 2012 report of neonatal regeneration following LAD ligation, we observed a small scar at the site of the LAD ligature, which we attributed to the persistence of the ligature. The Leor group made a similar observation, albeit they may have observed a larger anterior wall scar in close proximity to the ligature. Interestingly, almost immediately after online publication of our initial neonatal myocardial infarction report, another group reported complete regeneration with lack of anterior wall scarring following LAD ligation. This complete lack of scarring may be due to the group’s ability to directly visualize the LAD and therefore minimize the amount of myocardium included in the ligature. Although it is difficult to discern the precise technical discrepancies between the 3 The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Departments of Internal Medicine (H.A.S.) and Pediatrics (S.S.), The University of Texas Southwestern Medical Center, Dallas, TX. Correspondence to: Hesham A. Sadek, MD, PhD, Department of Internal Medicine/Cardiology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, NB10.230A, Dallas, TX 75039. E-mail: hesham.sadek@ut southwestern.edu J Am Heart Assoc. 2015;4:e001727 doi: 10.1161/JAHA.114.001727. a 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.