Abstract 284: The Role of Cardiomyocyte Proliferation in Pediatric Heart Growth

Abstract

Introduction Cardiomyocyte proliferation is an active cellular mechanism in systems that effectively regenerate myocardium, such as zebrafish, newt, and neonatal mice. However, this cellular growth mechanism has not been examined systematically in humans < 20 years of age. Examining the role of cardiomyocyte proliferation in post-natal heart growth in humans may provide a new cellular mechanism that could be targeted therapeutically. Hypothesis We hypothesized that cardiomyocyte proliferation contributes to myocardial growth in humans during post-natal development. Methods We examined 20 human hearts (3 weeks to 20 years of age) that were free from myocardial disease. We used confocal microscopy and laser-scanning cytometry to quantify cell cycle activity and associated cellular changes (cardiomyocyte ploidy and cellular volume). Results Measurements of mitosis, made by automated quantification of phosphorylated histone-3-positive cardiomyocytes, showed that during the first year of life the mean percentage of cardiomyocytes undergoing mitosis was 0.04 ± 0.01% (n = 6), declining to 0.008 ± 0.001% (n = 3) between 10 and 20 years of age. Cardiomyocyte cytokinesis, visualized by an antibody against MKLP-1 (a component of the centralspindlin complex), was detectable up to 20 years of age (n = 8), but not later in life (n = 4). The number of cardiomyocytes, quantified with stereology, increased four-fold between birth and 20 years. The mean cardiomyocyte volume increased concomitantly 12-fold. By relating these mechanistic data to left ventricular mass (determined by echocardiography), we modeled myocardial growth between birth and 20 years, which showed that the mean contribution of cardiomyocyte proliferation was 37%. Conclusions Our findings show that cardiomyocyte proliferation is a significant mechanism of developmental heart growth in humans after birth. This suggests that young humans may have the capacity to regenerate myocardium since the underlying mechanism, cardiomyocyte proliferation, is active under the age of 20 years. Cardiomyogenic stem cells may be involved in this process.