(L-470) Murine Cardiac and Cervical Remodeling during Gestation and Postpartum Periods

Introduction:: The postpartum period is a unique and complex period experienced only by those that have undergone pregnancy. During pregnancy, a patient’s heart and cervix undergo significant remodeling processes in support of fetal growth and in preparation for delivery. This remodeling that occurs is often considered temporary, despite there being little research characterizing the cervix or heart in the postpartum, or lactating, period. In normal pregnancy, the heart hypertrophies, increasing in both mass and volume to accommodate an increase in blood volume during fetal gestation. Following delivery, most researchers suggest that these changes revert to their pre-pregnancy values; however, this assumption has not been quantified in detail. In tandem with cardiac changes, the cervix has been studied extensively in detail during pregnancy exhibiting remodeling in four overlapping stages: softening, ripening, and dilation during gestation. However, the repair mechanisms following delivery have not yet been characterized. In vivo imaging provides a noninvasive technique to study these changes longitudinally. The consequence of cardiac and cervical remodeling on maternal health is still ambiguous. Roughly half of all pregnancy-related mortalities are attributed to cardiovascular dysfunction. Furthermore, insufficient cervical remodeling during pregnancy can lead to preterm birth, which may affect cardiac disease risk later in life. This study aims to quantify murine remodeling in vivo to compare cervical and cardiac remodeling in the same animal, improving our understanding of the effects tissue remodeling may have on overall maternal health.


Materials and Methods:: Virgin female C57Bl/6J mice (n=4) were paired with C57Bl/6J male mice in a 2:1 breeding scheme (Jackson Laboratories). All pregnant mice were imaged using ultrasound before pairing (baseline) and on gestational days (E) 6.5, 12.5, 15.5, and 18.5 using a high frequency system (Vevo3100, FUJIFILM VisualSonics, Toronto, ON, Canada). Both cervix images and long and short axis views of the left ventricle were taken using 3D and 4D modes. 3D images are obtained with sequential 2D B-mode images. 4D US provides a video of one cardiac cycle obtained with sequential 2D EKV (ECG-gated kilohertz visualization) videos.

Dams were randomly separated into either lactating (n=2) or non-lactating (n=2) group. Dams in the non-lactating group had their litter separated and sacrificed immediately after delivery, while those in the lactating group were allowed to nurse until postpartum day (PD) 21. PD 1 was established as the day after delivery and ultrasound images were taken on PD 1, 4, 7, 14, and 21. Following PD 21 imaging, each dam was sacrificed. Cardiac images were analyzed using a custom MATLAB graphical user interface to measure left ventricle mass and stroke volume. Cervical images from one mouse in each group were analyzed using SimVascular, VMTK, and NeuroMorph software to determine length and cross-sectional area.


Results, Conclusions, and Discussions:: Cardiac ultrasound image analysis reveals that left ventricle mass increases throughout pregnancy (Figure 1A). Following delivery, ventricle mass regresses in non-lactating mice but continues to increase in lactating mothers. At PD 21, lactating mice present with left ventricle masses larger than pre-pregnancy values. Conversely, left ventricle mass of non-lactating mice at PD 21 reverts to values closer to baseline. Stroke volume increases throughout days E0 to E18.5 in both groups, and in the postpartum period stroke volume continued to increase in lactating mice but decreased to baseline values in non-lactating mice (Figure 1B). Cervix analysis shows a decrease in length from baseline – E18.5, an increase directly following delivery at PD 1, and then decreases again in the first week of postpartum (Figure 1C).

Our data suggest lactating and non-lactating mice experience different cardiac remodeling after delivery. The continued increase in ventricle mass in lactating animals is likely due to the larger energy requirements of nursing. The increased energy expenditure drives an increased need for blood volume, thus hypertrophying the heart. The retention of increased ventricle mass at PD 21 in lactating mice suggests that lactation’s impact on cardiac health may be significant. It also suggests using postpartum values as baseline, as done in previous research, should not be common practice. Cervical length increase following delivery is likely due to the extreme mechanical loading of birth. Following the stretching of the tissue, the cervix repairs in the postpartum period. At PD 21 it is possible that normal estrus cycle has returned, resulting in length variation. There appears to be no correlation between lactation and cervical remodeling during the postpartum period. More animals and timepoints need to be analyzed to draw conclusions. Furthermore, future studies may control for litter size by normalizing data to the number of pups.

These data suggest lactation status does affect cardiac remodeling in the postpartum period, but it does not have a clear impact on cervical remodeling. These findings highlight the potential implications of lactation on maternal cardiac health and the need to account for lactation status when assessing heart function.


Acknowledgements (Optional): : We would like to acknowledge both the Purdue University’s Engineering Undergraduate Research Office (EURO) and Purdue’s Office of Undergraduate Research (OUR) for helping to fund this research. We acknowledge funding from the Gates Foundation, Indiana CTSI and Purdue University Women’s Global Health Institute. JLA was supported by the National Science Foundation under the Graduate Research Fellowship Program (GRFP; DGE-1842166).


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