Present therapeutics treating cardiovascular diseases (CVDs) are mainly symptomatic that do not fully prevent or reverse the diseases. Thus, developing novel therapeutic strategies and therapies is of high priority. In contrast to the adult mammalian heart, hearts of newborn mice can fully regenerate after a cardiac ischemic injury, including long-term normal heart functions. This regenerative capacity gets lost within the first week after birth. The underlying molecular mechanisms orchestrating this switch are barely understood. In recent years, long non-coding RNAs (lncRNAs) have emerged as powerful regulators of biological processes, including the gene expression network in both heart development and CVDs. Thus, lncRNAs are of high interest as potential therapeutic targets. 
This study aims to characterize the functions of the conserved, cardioprotective lncRNA H19 in neonatal cardiac regeneration, which is significantly down regulated within the first postnatal week. For this purpose, permanent left anterior descending artery (LAD) ligation surgeries were performed in neonatal H19 knockout (KO) and wild type (WT) mice to induce a myocardial infarction (MI) and study the cardiac regenerative potential depending on H19 expression. Successful induction of a MI was confirmed by echocardiography one day after the surgery. A second echocardiography was performed prior to sacrificing the mice to assess cardiac functional parameters. Hearts were harvested for molecular biological and histopathological analysis.
LAD ligation surgeries were performed 1.5 days post natum and the animals were sacrificed 7 or 13 days afterwards. For both, H19 WT and H19 KO mice, an improvement of the ejection fraction was observed. However, H19 KO mice regenerated significantly less. Q-RT-PCR analysis of the 7-day study group revealed significantly increased levels of collagens and Mmp9 in LAD-ligated H19 KO mice compared to H19 WT mice, whereas no significant differences of these fibrotic marker genes were found in the 13-day group. In general, histomorphological analysis of LAD-ligated H19 WT animals showed no signs of tissue damage or scarring in the 7- and 13-day groups, while some LAD-ligated H19 KO mice in the 13-day group showed clear signs of fibrosis as confirmed by picro-sirius red staining.  
In summary, our data indicate that H19 is crucial for a complete cardiac regeneration after MI in newborns. Since its loss impairs neonatal cardiac regeneration, we hypothesize that its overexpression later, shortly before the closure of the regenerative window, might extend the regenerative potential, which is currently investigated.