0500: Children with tetralogy of Fallot exhibit accelerated maturation of the cardiac tissue into adult phenotype

Abstract

Shortly after birth, under changes in loading conditions of the heart, a shift from predominantly hyperplasic to hypertrophic cardiac growth occurs. In rodents, at birth, neonatal proliferative cardiomyocytes (CMs) exhibit a fusiform shape and differentiated into non-proliferative rhod-shape CM around P20 defined as the mature state. In human, CM differentiation supposedly ended around 6 years old but the exact timing still remains unknown. Moreover, numerous stimuli most probably contribute to the CM maturation, including pressure. In a human model of pressure overload named tetralogy of Fallot (ToF), we thus hypothesized the occurence of an earlier maturation of the cardiac tissue. Methods we prospectively included 15 children around 6 month-old (min. 3.5 max. 27), who required surgery for the management of ToF. We assessed criteria of maturation from right ventricle tissue of infundibulum that was resected during the surgery. As previously described, heart sections analysis revealed a marked sub-endocardial fibrosis (473±444µm) and a significant fibrosis of the interstitium (13.0±6.3%). This criteria was correlated to the severity of the disease represented by the degree of desaturation (r=0,623; p=0,017). In all children analysed, CMs were hypertrophied but unlike healthy myocardium, CM size was heterogeneous (CV=40,4%), with alternating immature and mature area. In mature area, as expected, CMs proliferation stopped as indicated by the loss of Ki67 staining and exhibit a mature rod-shape. Ultrastructurally, CMs had structured intercalated disk and elongated contractile apparatus with an alignment of Z-strikes and apparent I-band. The lateral membrane between two CMs was compacted with periodic crests and holes. Our data highly suggest that the increase of pressure during childhood may act as a maturation factor. Myocardium in ToF is characterized by a shortening of the hyperplasia stage and a subsequent early hypertrophy stage.