Impaired myocardial development resulting in neonatal cardiac hypoplasia alters postnatal growth and stress response in the heart

Abstract

Impaired prenatal development leading to neonatal cardiac hypoplasia alters postnatal cardiac growth and stress response in vivo, thereby linking foetal programming to organ size control in the heart.

Prenatal Mechanistic Target of Rapamycin Complex 1 (m TORC1) Inhibition by Rapamycin Treatment of Pregnant Mice Causes Intrauterine Growth Restriction and Alters Postnatal Cardiac Growth, Morphology, and Function

“…Importantly, the rapamycin‐induced reduction in BW, HW, and HW/BW ratio was similar in cHccs +/− females compared to rapamycin‐treated controls ( Hccs +/+ ) (Figure B). The reduction in heart weight in neonatal cHccs +/− compared to Hccs +/+ females due to the reduced number of cardiomyocytes described previously was evident in both treatment groups but was not aggravated by rapamycin. At the cellular level, rapamycin does not specifically impair proliferation in cHccs +/− hearts at P1 (Figure C) but further induces apoptosis (Figure D) and reduces cardiomyocyte CSA (Figure E) when compared to rapamycin‐treated Hccs +/+ females.…”

“…Rapamycin‐treated Hccs +/+ and cHccs +/− neonates demonstrated similar reductions in heart weight ( HW ) and HW / BW ratio compared to vehicle‐treated animals. Note that the reduced HW and HW / BW ratio in cHccs +/− compared to Hccs +/+ newborns reported previously persisted after prenatal m TORC 1 inhibition (vehicle groups n=9, rapamycin groups n=10). C, Quantification of Ki67‐positive nuclei revealed unchanged proliferation rates within the LV myocardium of vehicle‐ and rapamycin‐treated hearts and between genotypes (vehicle groups n=6, rapamycin Hccs +/+ n=12, rapamycin cHccs +/− n=13).…”

“…Cardiomyocyte cross‐sectional area (CSA) was significantly larger in Hccs +/+ as well as cHccs +/− hearts exposed to prenatal rapamycin compared to vehicle treatment. Note that compensatory cardiomyocyte hypertrophy in c Hccs +/− mice reported previously is evident in the vehicle group but lost in rapamycin‐treated hearts (vehicle Hccs +/+ n=6, rapamycin Hccs +/+ n=7, vehicle and rapamycin c Hccs +/− n=5). B, Representative images of Sirius Red–stained LV myocardium of adult mice.…”

“…Compensatory proliferation of the healthy cardiomyocyte population allows embryonic heart regeneration, however, such that the neonatal cHccs +/− heart is composed of 90% healthy cells and contains only 10% diseased cells . Nevertheless, embryonic heart regeneration is not sufficient to completely build up the myocardium, resulting in cHccs +/− hearts being hypoplastic at birth due to a reduced number of cardiomyocytes . This reduction in cell number is postnatally compensated for by accelerated and augmented cardiomyocyte hypertrophic growth, such that heart size normalizes by early adulthood .…”

“…Nevertheless, embryonic heart regeneration is not sufficient to completely build up the myocardium, resulting in cHccs +/− hearts being hypoplastic at birth due to a reduced number of cardiomyocytes . This reduction in cell number is postnatally compensated for by accelerated and augmented cardiomyocyte hypertrophic growth, such that heart size normalizes by early adulthood . Given the established role of mTORC1 in heart and organ size control, we speculated that mTORC1 activity might be important for fetal cardiac growth and regulation of neonatal heart size in general as well as for compensatory growth of cHccs +/− hearts in particular.…”