Placental growth factor influences maternal cardiovascular adaptation to pregnancy in mice.

In healthy human pregnancies, placental growth factor (PGF) concentrations rise in maternal plasma during early gestation, peak over Weeks 26-30, then decline. Because PGF in nongravid subjects participates in protection against and recovery from cardiac pathologies, we asked if PGF contributes to pregnancy-induced maternal cardiovascular adaptations. Cardiovascular function and structure were evaluated in virgin, pregnant, and postpartum C56BL/6-Pgf(-) (/) (-) (Pgf(-) (/) (-)) and C57BL/6-Pgf(+/+) (B6) mice using plethysmography, ultrasound, quantitative PCR, and cardiac and renal histology. Pgf(-/-) females had higher systolic blood pressure in early and late pregnancy but an extended, abnormal midpregnancy interval of depressed systolic pressure. Pgf(-/-) cardiac output was lower than gestation day (gd)-matched B6 after midpregnancy. While Pgf(-) (/) (-) left ventricular mass was greater than B6, only B6 showed the expected gestational gain in left ventricular mass. Expression of vasoactive genes in the left ventricle differed at gd8 with elevated Nos expression in Pgf(-) (/) (-) but not at gd14. By gd16, Pgf(-) (/) (-) kidneys were hypertrophic and had glomerular pathology. This study documents for the first time that PGF is associated with the systemic maternal cardiovascular adaptations to pregnancy.

Analysis of maternal and fetal cardiovascular systems during hyperglycemic pregnancy in the nonobese diabetic mouse.

Preconception or gestationally induced diabetes increases morbidities and elevates long-term cardiovascular disease risks in women and their children. Spontaneously hyperglycemic (d)-NOD/ShiLtJ female mice, a type 1 diabetes model, develop bradycardia and hypotension after midpregnancy compared with normoglycemic, age- and gestational day (GD)-matched control (c-NOD) females. We hypothesized that onset of the placental circulation at GD 9-10 and rapid fetal growth from GD 14 correlate with aberrant hemodynamic outcomes in d-NOD females. To develop further gestational time-course correlations between maternal cardiac and renal parameters, high-frequency ultrasonography was applied to d- and c-NOD mice (virgin and at GD 8-16). Cardiac output and left ventricular (LV) mass increased in c-NOD but not in d-NOD mice. Ultrasound and postmortem histopathology showed overall greater LV dilation in d-NOD than in c-NOD mice at mid to late gestation. These changes suggest blunted remodeling and altered functional adaptation of d-NOD hearts. Umbilical cord ultrasounds revealed lower fetal heart rates from GD 12 and lower umbilical flow velocities at GD 14 and GD 16 in d-NOD versus c-NOD pregnancies. From GD 14 to GD 16, d-NOD fetal losses exceeded c-NOD fetal losses. Similar aberrant responses in pregnancies of women with diabetes may elevate postpartum maternal and child cardiovascular risk, particularly if mothers lack adequate prenatal care or have poor glycemic control during gestation.

Strain Estimation of the Murine Right Ventricle Using High-Frequency Speckle-Tracking Ultrasound.

Right ventricular (RV) strain measurements from ultrasound via speckle-tracking techniques are being used more frequently as a non-invasive diagnostic tool for a variety of cardiopulmonary pathologies. However, despite the clinical utility of ultrasound RV strain measurements, quantification of RV strain in rodents remains difficult owing to unique image artifacts and non-standardized methodologies. We demonstrate here a simple approach for measuring RV strain in both mice and rats using high-frequency ultrasound and automated speckle tracking. Our results show estimated peak RV free-wall longitudinal strain values (mean ± standard error of the mean) in mice (n = 15) and rats (n = 5) of, respectively, -10.38% ± 0.4% and -4.85% ± 0.42%. We further estimated the 2-D Green-Lagrange strain within the RV free wall, with longitudinal components estimated at -5.7% ± 0.48% in mice and -2.1% ± 0.28% in rats. These methods and data may provide a foundation for future work aimed at evaluating murine RV strain levels in different disease models.

High-Frequency 4-Dimensional Ultrasound (4DUS): A Reliable Method for Assessing Murine Cardiac Function.

In vivo imaging has provided a unique framework for studying pathological progression in various mouse models of cardiac disease. Although conventional short-axis motion-mode (SAX MM) ultrasound and cine magnetic resonance imaging (MRI) are two of the most prevalent strategies used for quantifying cardiac function, there are few notable limitations including imprecision, inaccuracy, and geometric assumptions with ultrasound, or large and costly systems with substantial infrastructure requirements with MRI. Here we present an automated 4-dimensional ultrasound (4DUS) technique that provides comparable information to cine MRI through spatiotemporally synced imaging of cardiac motion. Cardiac function metrics derived from SAX MM, cine MRI, and 4DUS data show close agreement between cine MRI and 4DUS but overestimations by SAX MM. The inclusion of a mouse model of cardiac hypertrophy further highlights the precision of 4DUS compared with that of SAX MM, with narrower groupings of cardiac metrics based on health status. Our findings suggest that murine 4DUS can be used as a reliable, accurate, and cost-effective technique for longitudinal studies of cardiac function and disease progression.

In Utero Exposure to a Cardiac Teratogen Causes Reversible Deficits in Postnatal Cardiovascular Function, But Altered Adaptation to the Burden of Pregnancy.

Congenital heart defects (CHD) are the most common birth anomaly and while many resolve spontaneously by 1 year of age, the lifelong burden on survivors is poorly understood. Using a rat model of chemically induced CHD that resolve postnatally, we sought to characterize the postnatal changes in cardiac function, and to investigate whether resolved CHD affects the ability to adapt to the increased the cardiovascular (CV) burden of pregnancy. To generate rats with resolved CHD, pregnant rats were administered distilled water or dimethadione (DMO) [300 mg/kg b.i.d. on gestation day (gd) 9 and 10] and pups delivered naturally. To characterize structural and functional changes in the heart, treated and control offspring were scanned by echocardiography on postnatal day 4, 21, and 10-12 weeks. Radiotelemeters were implanted for continuous monitoring of hemodynamics. Females were mated and scanned by echocardiography on gd12 and gd18 during pregnancy. On gd18, maternal hearts were collected for structural and molecular assessment. Postnatal echocardiography revealed numerous structural and functional differences in treated offspring compared with control; however, these resolved by 10-12 weeks of age. The CV demand of pregnancy revealed differences between treated and control offspring with respect to mean arterial pressure, CV function, cardiac strain, and left ventricular gene expression. In utero exposure to DMO also affected the subsequent generation. Gd18 fetal and placental weights were increased in treated F2 offspring. This study demonstrates that in utero chemical exposure may permanently alter the capacity of the postnatal heart to adapt to pregnancy and this may have transgenerational effects.

In utero dimethadione exposure causes postnatal disruption in cardiac structure and function in the rat.

In utero exposure of rat embryos to dimethadione (DMO), the N-demethylated teratogenic metabolite of the anticonvulsant trimethadione, induces a high incidence of cardiac heart defects including ventricular septal defects (VSDs). The same exposure regimen also leads to in utero cardiac functional deficits, including bradycardia, dysrhythmia, and a reduction in cardiac output (CO) and ejection fraction that persist until parturition (10 days after the final dose). Despite a high rate of spontaneous postnatal VSD closure, we hypothesize that functional sequelae will persist into adulthood. Pregnant Sprague Dawley rats were administered six 300 mg/kg doses of DMO, one every 12 h in mid-pregnancy beginning on the evening of gestation day 8. Postnatal cardiac function was assessed in control (CTL) and DMO-exposed offspring using radiotelemetry and ultrasound at 3 and 11 months of age, respectively. Adult rats exposed to DMO in utero had an increased incidence of arrhythmia, elevated blood pressure and CO, greater left ventricular volume and elevated locomotor activity versus CTL. The mean arterial pressure of DMO-exposed rats was more sensitive to changes in dietary salt load compared with CTL. Importantly, most treated rats had functional deficits in the absence of a persistent structural defect. It was concluded that in utero DMO exposure causes cardiovascular deficits that persist into postnatal life in the rat, despite absence of visible structural anomalies. We speculate this is not unique to DMO, suggesting possible health implications for infants with unrecognized gestational chemical exposures.