Abstract 19: Myocyte Turnover in the Aging Human Heart

The controversy on the growth reserve of the adult human heart has not been resolved and the extent of myocyte renewal reported by different groups varies significantly. Additionally, myocyte regeneration has been claimed to decrease with aging, although cell death is markedly enhanced in the old myocardium. Thus, the effects of age and gender on the magnitude of myocyte turnover were determined. Myocyte replication, senescence and apoptosis were measured in normal female and male human hearts collected from patients 19 to 104 years of age who died from causes other than cardiovascular diseases. Myocardial aging was characterized by a time-dependent increase in the generation of amplifying cardiomyocytes in women and men. Levels of Ki67 and phospho-H3 were comparable in the young female and male heart but differed later in life. As a function of age, the pool of amplifying myocytes was 2-fold higher in women than men, pointing to enhanced myocyte renewal in the female heart. The frequency of p16 INK4a -positive myocytes was higher in men than in women. From 19 to 104 years of age, the time-dependent increase in senescent myocytes was 0.68% per year in women and 0.89% per year in men; the 31% higher rate of accumulation of old myocytes in the aging male heart was significant. Myocyte apoptosis occurred only in p16 INK4a -positive cells and was consistently higher in men than in women at all age intervals. However, the increase in myocyte apoptosis with age did not differ with gender. Based on these parameters, we measured the average age of cardiomyocytes, their age distribution, turnover rate and time to acquire the senescent phenotype to define the biology of myocardial aging as a function of lifespan. In the female heart, myocyte turnover occurs at a rate of 10%, 15% and 40% per year at 20, 60 and 100 years of age, respectively. Corresponding values in the male heart are 7%, 12% and 32% per year, documenting that cardiomyogenesis involves a large and progressively increasing number of parenchymal cells with aging. In conclusion, the human heart is a highly dynamic organ in which progressive myocyte loss is at least in part counteracted by enhanced myocyte renewal. Myocyte regeneration in the physiologically aging heart takes place at previously unexpected levels in both women and men.