This study investigates the origin of new cardiomyocytes in adult mammals, using a combination of genetic fate-mapping and Multi-isotope Imaging Mass Spectrometry (MIMS). The authors found that the generation of new cardiomyocytes primarily occurs through the division of pre-existing cardiomyocytes, rather than through stem cell activity. They observed a low rate of cardiomyocyte turnover, which decreased with age, and increased near areas of myocardial injury. MIMS allowed for the detection of nonradioactive stable isotope tracers, enabling high-resolution quantitative mass imaging. The study demonstrated that new cardiomyocytes are predominantly derived from pre-existing cardiomyocytes, with a projected rate of approximately 0.76% per year in young adult mice. This finding suggests that cardiac progenitors play a limited role in myocardial homeostasis and repair in mammals.This study investigates the origin of new cardiomyocytes in adult mammals, using a combination of genetic fate-mapping and Multi-isotope Imaging Mass Spectrometry (MIMS). The authors found that the generation of new cardiomyocytes primarily occurs through the division of pre-existing cardiomyocytes, rather than through stem cell activity. They observed a low rate of cardiomyocyte turnover, which decreased with age, and increased near areas of myocardial injury. MIMS allowed for the detection of nonradioactive stable isotope tracers, enabling high-resolution quantitative mass imaging. The study demonstrated that new cardiomyocytes are predominantly derived from pre-existing cardiomyocytes, with a projected rate of approximately 0.76% per year in young adult mice. This finding suggests that cardiac progenitors play a limited role in myocardial homeostasis and repair in mammals.