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A significant number of pregnancies occur at advanced maternal age (>35 yr), which is a risk factor for pregnancy complications. Healthy pregnancies require massive hemodynamic adaptations, including an increased blood volume and cardiac output. There is growing evidence that these cardiovascular adaptations are impaired with age, however, little is known about maternal cardiac function with advanced age. We hypothesized that cardiac adaptations to pregnancy are impaired with advanced maternal age. Younger (4 mo; ∼early reproductive maturity in humans) and aged (9 mo; ∼35 yr in humans) pregnant Sprague-Dawley rats were assessed and compared with age-matched nonpregnant controls. Two-dimensional echocardiographic images were obtained (ultrasound biomicroscopy; under anesthesia) on gestational day 19 (term = 22 days) and compared with age-matched nonpregnant rats ( n = 7-9/group). Left ventricular structure and function were assessed using short-axis images and transmitral Doppler signals. During systole, left ventricular anterior wall thickness increased with age in the nonpregnant rats, but there was no age-related difference between the pregnant groups. There were no significant pregnancy-associated differences in left ventricular wall thickness. Calculated left ventricular mass increased with age in nonpregnant rats and increased with pregnancy only in young rats. Compared with young pregnant rats, the aortic ejection time of aged pregnant rats was greater and Tei index was lower. Overall, the greater aortic ejection time and lower Tei index with age in pregnant rats suggest mildly altered cardiac adaptations to pregnancy with advanced maternal age, which may contribute to adverse outcomes in advanced maternal age pregnancies. NEW & NOTEWORTHY We demonstrated that even before the age of reproductive senescence, rats show signs of age-related alterations in cardiac structure that suggests increased cardiac work. Our data also demonstrate, using an in vivo echocardiographic approach, that advanced maternal age in a rat model is associated with altered cardiac function and structure relative to younger pregnant controls.

Prenatal hypoxia is associated with enhanced susceptibility to cardiac ischemia-reperfusion (I/R) injury in adult offspring, however, the mechanisms remain to be fully investigated. Endothelin-1 (ET-1) is a vasoconstrictor that acts via endothelin A (ET A ) and endothelin B (ET B ) receptors and is essential in maintaining cardiovascular (CV) function. Prenatal hypoxia alters the ET-1 system in adult offspring possibly contributing to I/R susceptibility. We previously showed that ex vivo application of ET A antagonist ABT-627 during I/R prevented the recovery of cardiac function in prenatal hypoxia-exposed males but not in normoxic males nor normoxic or prenatal hypoxia-exposed females. In this follow-up study, we examined whether placenta-targeted treatment with a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ) during hypoxic pregnancies could alleviate this hypoxic phenotype observed in adult male offspring. We used a rat model of prenatal hypoxia where pregnant Sprague-Dawley rats were exposed to hypoxia (11% O 2 ) from gestational days ( GD ) 15-21 after injection with 100 μL saline or nMitoQ (125 μM) on GD15 . Male offspring were aged to 4 mo and ex vivo cardiac recovery from I/R was assessed. Offspring born from hypoxic pregnancies and treated with nMitoQ had increased cardiac recovery from I/R in the presence of ABT-627 compared with their untreated counterparts where ABT-627 prevented recovery. Cardiac ET A levels were increased in males born from hypoxic pregnancies with nMitoQ treatment compared with saline controls (Western blotting). Our data indicate a profound impact of placenta-targeted treatment to prevent an ET A receptor cardiac phenotype observed in adult male offspring exposed to hypoxia in utero. NEW & NOTEWORTHY In this follow-up study, we showed a complete lack of recovery from I/R injury after the application of an ET A receptor antagonist (ABT-627) in adult male offspring exposed to hypoxia in utero while maternal treatment with nMitoQ during prenatal hypoxia exposure prevented this effect. Our data suggest that nMitoQ treatment during hypoxic pregnancies may prevent a hypoxic cardiac phenotype in adult male offspring.

Fetal hypoxia, a major consequence of complicated pregnancies, impairs offspring cardiac tolerance to ischemia-reperfusion (I/R) insult; however, the mechanisms remain unknown. Endothelin-1 (ET-1) signaling through the endothelin A receptors (ET A ) is associated with cardiac dysfunction. We hypothesized that prenatal hypoxia exacerbates cardiac susceptibility to I/R via increased ET-1 and ET A levels, whereas ET A inhibition ameliorates this. Pregnant Sprague-Dawley rats were exposed to normoxia (21% O 2 ) or hypoxia (11% O 2 ) on gestational days 15-21 . Offspring were aged to 4 mo, and hearts were aerobically perfused or subjected to ex vivo I/R, with or without preinfusion with an ET A antagonist (ABT-627). ET-1 levels were assessed with ELISA in aerobically perfused and post-I/R left ventricles (LV). ET A and ET B levels were assessed by Western blotting in nonperfused LV. As hypothesized, ABT-627 infusion tended to improve post-I/R recovery in hypoxic females ( P = 0.0528); however, surprisingly, ABT-627 prevented post-I/R recovery only in the hypoxic males ( P < 0.001). ET-1 levels were increased in post-I/R LV in both sexes regardless of the prenatal exposure ( P < 0.01). ET A expression was similar among all groups, whereas ET B (isoform C) levels were decreased in prenatally hypoxic females ( P < 0.05). In prenatally hypoxic males, ET A signaling may be essential for tolerance to I/R, whereas in prenatally hypoxic females, ET A may contribute to cardiac dysfunction. Our data illustrate that understanding the prenatal history has critical implications for treatment strategies in adult chronic diseases. NEW & NOTEWORTHY We demonstrated that prenatal hypoxia (a common condition of pregnancy) can have profound differential effects on treatment strategies in adult cardiovascular disease. Our data using a rat model of prenatal hypoxia demonstrated that, as adults, although inhibition of endothelin (ET A ) receptors before an ex vivo cardiac ischemic insult improved recovery in females, it strikingly prevented recovery in males. Our data indicate a sex-specific effect of prenatal hypoxia on the cardiac ET-1 system in adult offspring.

Intrauterine growth restriction (IUGR) has been associated with increased susceptibility to myocardial ischemia-reperfusion (I/R) injury. Exercise is an effective preventive intervention for cardiovascular diseases; however, it may be detrimental in conditions of compromised health. The aim of this study was to determine whether exercise training can improve cardiac performance after I/R injury in IUGR offspring. We used a hypoxia-induced IUGR model by exposing pregnant Sprague-Dawley rats to 21% oxygen (control) or hypoxic (11% oxygen; IUGR) conditions from gestational day 15 to 21. At 10 wk of age, offspring were randomized to a sedentary group or to a 6-wk exercise protocol. Transthoracic echocardiography assessments were performed after 6 wk. Twenty-four hours after the last bout of exercise, ex vivo cardiac function was determined using a working heart preparation. With exercise training, there was improved baseline cardiac performance in male control offspring but a reduced baseline cardiac performance in male IUGR exercised offspring (P < 0.05). In male offspring, exercise decreased superoxide generation in control offspring, while in IUGR offspring, it had the polar opposite effect (interaction P ≤ 0.05). There was no effect of IUGR or exercise on cardiac function in female offspring. In conclusion, in male IUGR offspring, exercise may be a secondary stressor on cardiac function. A reduction in cardiac performance along with an increase in superoxide production in response to exercise was observed in this susceptible group., (Copyright © 2015 the American Physiological Society.)