ABSTRACT After myocardial infarction in the adult heart the remaining, non-infarcted tissue adapts to compensate the loss of functional tissue. This adaptation requires changes in gene expression networks, which are mostly controlled by transcription regulating proteins. Long non-coding transcripts (lncRNAs) are now recognized for taking part in fine-tuning such gene programs. We identified and characterized the cardiomyocyte specific lncRNA Sweetheart RNA ( Swhtr ), an approximately 10 kb long transcript divergently expressed from the cardiac core transcription factor coding gene Nkx2-5 . We show that Swhtr is dispensable for normal heart development and function, but becomes essential for the tissue adaptation process after myocardial infarction. Re-expressing Swhtr from an exogenous locus rescues the Swhtr null phenotype. Genes depending on Swhtr after cardiac stress are significantly occupied, and therefore most likely regulated by NKX2-5. Our results indicate a synergistic role for Swhtr and the developmentally essential transcription factor NKX2-5 in tissue adaptation after myocardial injury.