SEX-DIFFERENCES IN FETAL PROGRAMMING OF CARDIOMYOPATHY INDUCED BY HYPERTENSIVE DISORDERS OF PREGNANCY IN MICE

Abstract

Hypertensive disorders can reach one in ten pregnancies worldwide. They account for a quarter of all preterm births and low birth weight, significantly increasing rates of maternal and neonatal morbidity and mortality Children born to hypertensive pregnancies can develop special clinical features that are consistent with a preterm or accelerated aging process with signs of cardiac remodeling as early as childhood. Significant heart shape and ventricular geometrical alterations have been described in growth-restricted fetuses of hypertensive pregnancies suggesting an extended impact on fetal heart development and programming of heart diseases. The aim of this study was to develop a new ultrasound imaging protocol to describe, for the first time in a genetic mice model of maternal hypertension and superposed preeclampsia, sex-differences in the fetal programming of cardiomyopathy. We have performed echocardiography imaging in fetuses of n=4/group transgenic pregnant mice overexpressing human renin and angiotensinogen and controls (C57BL/6) at 18.5 gestational days. Fetal images were adjusted by intracranial diameter as a surrogate intrauterine marker of fetal growth. Genotype-negative offspring were followed up to 40-day postnatal, when echocardiography was performed in male and female offspring (n=8/group) of control and transgenic mothers. Data are presented as average±SD of control vs hypertensive-pregnancies, compared using student t-test. Fetuses of hypertensive mothers have larger LV mass (3.2±0.4 vs 4.3±0.3 mg, P < .001) with thicker LV walls (0.32±0.02 vs 0.45±0.04 mm, P < .01) and dilated chamber (0.82±0.02 vs 0.97±0.07 mm, P < .01) compared to fetuses of control mothers, these parameters remaining significant after adjusting by intracranial diameter. Into adulthood, both male and female offspring to hypertensive mothers have greater LV mass (male: 88±19 vs 139±62 mg P < .01; female: 74±21 vs 104±27 P < .05) and wall thickness (male: 0.70±0.03 vs 0.95±0.22 mm P < .05; female: 0.63±0.15 vs 0.91±0.17 mm P < .05) compared to control offspring. However, in females only, these changes were added by an important LV chamber dilation (3.3±0.3 vs 3.9±0.4 mm P < .05) and reduced fraction of shortening (48±9 vs 33±4 % P < .01), indicating systolic ventricular dysfunction only in female offspring in comparison to controls. Our findings demonstrate for the first time, the feasibility of using fetal and postnatal echocardiography to assess the programming of cardiomyopathy in mice exposed to hypertensive pregnancies. Further, we have described that the transgenic model of maternal hypertension and preeclampsia can induce significant fetal heart remodeling changes that can persist into adulthood in offspring, and in females only, into an accelerated programming of cardiomyopathy.