S21 - Of mice and women: left ventricle remodeling during chronic hypertension in murine pregnancy

Introduction: : Of all pregnancies, 2-5% are complicated by chronic hypertension [1], which increases the risk of peripartum cardiomyopathy and maternal morbidity [2-3]. Hypertension-induced pressure overload reduces stroke volume, whereas volume overload from pregnancy increases stroke volume. However, the combined impact of these opposing effects on cardiac function and strain remains unclear. To address this, we used a mouse model of pregnancy with pre-existing hypertension to characterize cardiac remodeling, hypothesizing that pregnancy may counteract hypertension-related declines in cardiac function.

Materials and

Methods: : Nulliparous female C57Bl6/J mice (10-13 weeks old) were randomly assigned into pregnancy control (PREG, n=5), hypertensive control (HT, n=7), and hypertensive pregnancy (HT+PREG, n=5) groups. We induced hypertension via subcutaneous implantation of 42-day miniosmotic pumps (model 2006; Azlet Durect) loaded with angiotensin II (1000 ng/kg/min). We quantified cardiac function and left ventricular strain from 2D and 4D high-frequency ultrasound images (MX550D, 40 MHz center frequency, Vevo3100, FUJIFILM VisualSonics) and tail-cuff blood pressure at baseline, 14 days after pump implantation, throughout embryogenesis, and on postpartum day 1. For the HT group, imaging timepoints were matched to the average age at embryonic (e) day 1 of HT+PREG animals. Statistical significance was assessed by two-way ANOVA (p < 0.05).

Results, Conclusions, and Discussions:: Mean arterial pressure (MAP) was elevated relative to baseline in HT (107 +/- 12mmHg, p< 0.05) and HT+PREG (116 +/- 11mmHg, p=0.08) 14 days after the introduction of angiotensin II, while MAP remained unchanged in PREG animals. Mean ejection fraction (EF) was maintained in PREG animals at 65.4 +/- 2.1% throughout the experimental timeline. By gestational day e18.5 (37 days after pump implant), EF decreased significantly in the HT group (44.9 +/- 8.7%; p< 0.05) and moderately in the HT+PREG group (52.5 +/- 8.0%; p=0.69, Fig. 1A). EF subsequently increased in the HT+PREG group after delivery (60.3 +/- 10.7%; p=0.91) compared to e18.5. In HT animals, stroke volume and cardiac output trended downward across the experimental timeline. However, when superimposed with pregnancy (HT+PREG), stroke volume and cardiac output followed trends similar to the PREG group (Fig. 1B-C). Compared to global circumferential and longitudinal strain (Ecc, Ell) in HT animals (Ecc = -22.8 +/- 8.3%; Ell = -17.6 +/- 3.0%), our results revealed that strains were slightly greater in HT+PREG animals (Ecc = -24.7 +/- 2.1%, p=0.94; Ell = -20.6 +/- 4.2%, p=0.57), but smaller than the PREG group (Ecc: -30.1 +/- 3.2%, p=0.46; Ell: -24.7 +/- 4.3, p=0.70), though not significantly (Fig. 1D-E). These results suggest that adaptations during pregnancy may alter the cardiac response to hypertension. Ongoing regional strain analysis, histology, and assessment of wall thickness may help identify the underlying differences between groups that are driving the changes observed in ejection fraction, stroke volume, and cardiac output. Findings from this work provide insight into the pathophysiology of chronic hypertension in pregnancy and set the foundation for future efforts aimed at identifying patient risk factors, ultimately improving the standard of care for both mother and child.

[1] Lawler, et al., Hypertens Pregnancy. 2007.
[2] Seely and Hecker, AHA Circ., 2014.
[3] Chappell, et al., Hypertension. 2008

Acknowledgements and/or References (Optional):: We would like to acknowledge Jake Castro, Sarah Grev, and Samantha Stebbings from Purdue University for their help with data analysis. We would also like to acknowledge the Purdue Women’s Global Health Institute for their financial support through the Pilot Grant Program.