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Hypertension management based on hemodynamic measurements
SMFM Abstracts S91
Volume 189, Number 6 Am J Obstet Gynecol 93
HYPERTENSION MANAGEMENT BASED ON HEMODYNAMIC MEASUREMENTS DAVID CHAFFIN1, 1Society for Maternal-Fetal Medicine, Huntington, WV OBJECTIVE: To evaluate the clinical outcomes of a program to pharmacologically manage hypertensive pregnant patients based on serial measurements of blood pressure, cardiac output (CO), and systemic vascular resistance (SVR) beginning in the second trimester. STUDY DESIGN: Patients were enrolled in the program based on a history of chronic hypertension, type 1 diabetes, chronic renal failure, or early severe preeclampsia. Blood pressure, cardiac output, and systemic vascular resistance were measured using thoracic electrical impedance plethysmography. Patients with hyperdynamic or mixed vasoconstrictive/hyperdynamic measurements at a gestational age of less than 24 weeks were treated with atenolol. Vasodilators were added for SVR >1100 dyne*sec*cmÿ5. Patients were followed on a regular basis until 34 weeks’ gestation with medication dosages adjusted to attempt to achieve normal hemodynamics. Patients were managed by referring physicians after 34 weeks. RESULTS: The first 106 patients treated with atenolol enrolled at less than 24 weeks are included in this report. The mean gestational age at enrollment was 16 ± 4 wks. The average mean arterial blood pressure was 99 ± 12 mm Hg. Initial cardiac output was 7.7 ± 1.5 liters/min (normal < 7.6 liters/min) with a range of 4.1 to 12.8 liters/min. Atenolol dosage ranged from 25 mg to 200 mg per day. Additional vasodilators used included hydralazine, nifedipine, and Isordil. Mean gestational age at delivery was 36 ± 3 weeks with a mean percentile birth weight of 47 (11% less than 10th centile). There were 4 patients delivered at less than 34 weeks for hypertensive complications. Three fetal deaths were due to premature labor at 22 to 23 weeks. 35 patients delivered between 34 and 37 weeks. The average hospital stay for these infants was 3.5 days (2.5 days for term infants). CONCLUSION: Early intervention with atenolol in an at-risk population with abnormal hemodynamics results in a low rate of early hypertensive complications with no increase in growth restriction.
95
ABNORMAL VASCULAR FUNCTION IN OFFSPRING OF ENDOTHELIAL NITRIC OXIDE SYNTHASE KNOCKOUT MICE: GENETIC FACTORS OR FETAL PROGRAMMING BY UTERINE ENVIRONMENT? MONICA LONGO1, JOSJE LANGENVELD2, YURI VEDERNIKOV1, GARLAND ANDERSON1, RADEK BUKOWSKI1, ROBERT GARFIELD1, GEORGE SAADE1, 1 University of Texas Medical Branch, Dept. of Obstetrics & Gynecology, Galveston, TX 2Maastricht University Medical Center, Dept. of Obstetrics & Gynecology, Maastricht, The Netherlands OBJECTIVE: We have previously shown that the abnormal vascular reactivity in heterozygous offspring of transgenic mice lacking an endothelial nitric oxide synthase (NOS3) is manifest only when the mother is knockout. Our objective was to determine whether genetic imprinting or abnormal uterine environment accounts for this fetal programming of vascular function. STUDY DESIGN: Homozygous NOS3 knockout (C57BL/6J-NOS3ÿ/ÿKO) and wild-type mice (NOS3+/+WT) were cross-bred to obtain 2 types of heterozygous embryos, maternally derived heterozygous (NOS3+/ÿmat) and paternally derived heterozygous (NOS3+/ÿpat). The NOS3+/ÿmat and NOS3+/ ÿpat embryos were harvested and transferred to the uteri of wild-type (NOS3+/ +WT ) foster mothers. Female and male mice from these litters were sacrificed at 78 weeks of age (n = 5-10/group) and 2-mm segments of carotid artery were mounted in a wire myograph to study vascular reactivity in vitro. Concentrationresponse curves to a1-adrenergic agonist phenylephrine (PE, 10ÿ10ÿ10ÿ5 M) and endothelium-dependent vasorelaxant acetylcholine (ACh, 10ÿ10ÿ10ÿ5 M) were obtained. The maximal effect, area under the concentration-response curve, and the EC50 (concentration producing 50% of the maximal effect) were calculated. Unpaired Student t-test and one-way ANOVA followed by NewmanKeuls post-hoc test were used for analysis (significance: P < 0.05). RESULTS: The vasorelaxant responses to ACh and the contractile responses to PE in later life were not significantly different in NOS3+/ÿmat and NOS3+/ÿpat female and male mice that developed in the uteri of genetically normal NOS3+/ +WT foster mothers. Transfer of heterozygous embryos into normal females abolished the previously reported effect of parental origin on vascular reactivity later in life. CONCLUSION: These data support the role of abnormal uterine environment rather than genetic imprinting in the fetal programming of abnormal vascular function in later life.
94
EFFECT OF PREGNANCY ON VASCULAR RESPONSES IN THE OFFSPRINGS OF ENDOTHELIAL NITRIC OXIDE SYNTHASE KNOCKOUT MICE MONICA LONGO1, JOSJE LANGENVELD2, VENU JAIN1, YURI VEDERNIKOV1, GARLAND ANDERSON1, GARY HANKINS1, ROBERT GARFIELD1, GEORGE SAADE1, 1University of Texas Medical Branch, Dept. of Obstetrics & Gynecology, Galveston, TX 2Maastricht University Medical Center, Dept. of Obstetrics & Gynecology, Maastricht, The Netherlands OBJECTIVE: Transgenic mice lacking the endothelial nitric oxide synthase (NOS3) have litters with growth deficiency and abnormal vascular reactivity in later life. The objective of the study was to evaluate the role of gravidity in modulating these responses. STUDY DESIGN: Litters from homozygous NOS3 knockout (C57BL/6JNOS3ÿ/ÿKO) and maternally derived heterozygous (NOS3+/ÿMat) mice were used. These litters were obtained from two groups of breeder mice: G1 (gravidity 0-2) and G2 (gravidity 5-9). Female mice from these litters (G1-NOS3ÿ/ÿKO, G1NOS3+/ÿMat, G2-NOS3ÿ/ÿKO, G2-NOS3+/ÿMat) were sacrificed at 7-8 weeks of age (n = 8-10/group) and 2-mm segments of carotid artery were mounted in a wire myograph for vascular reactivity study. Responses to phenylephrine (PE, 10ÿ10 to 10ÿ5 M) and acetylcholine (ACh, 10ÿ10 to 10ÿ5 M) were studied. The maximal effect (ME), area under the concentration-response curve, and the EC50 (concentration producing 50% of the maximal effect) were calculated. One-way ANOVA was used for statistical analysis (significance: P < 0.05). RESULTS: Ach produced vasorelaxation in a dose-dependent manner in G2-NOS3ÿ/ÿKO and G2-NOS3+/ÿMat, while ACh effects were completely abolished in the G1-NOS3ÿ/ÿKO and G1-NOS3+/ÿMat. PE contraction was significantly increased in G1-NOS3ÿ/ÿKO and G1-NOS3+/ÿMat compared with G2-NOS3ÿ/ÿKO and G2-NOS3+/ÿMat (ME: G1-NOS3ÿ/ÿKO, 178.3 ± 6.1 vs G2NOS3ÿ/ÿKO, 92 ± 8.8; G1-NOS3+/ÿMat, 210.7 ± 21.3 vs G2-NOS3+/ÿMat, 111 ± 6.6, P < 0.05). CONCLUSION: These data support the role of abnormal uterine environment in the fetal programming of vascular function in later life. The uterine environment in mice lacking a functional NOS improves with successive gestations, leading to improvement in vascular function in later life.
96
BIRTHWEIGHT AND POSTNATAL GROWTH IN OFFSPRING OF ENDOTHELIAL NITRIC OXIDE SYNTHASE KNOCKOUT MICE: GENETIC FACTORS OR FETAL PROGRAMMING BY UTERINE ENVIRONMENT? MONICA LONGO1, JOSJE LANGENVELD2, RADEK BUKOWSKI1, GARY HANKINS1, GARLAND ANDERSON1, ROBERT GARFIELD1, GEORGE SAADE1, 1University of Texas Medical Branch, Dept. of Obstetrics & Gynecology, Galveston, TX 2Maastricht University Medical Center, Dept. of Obstetrics & Gynecology, Maastricht, The Netherlands OBJECTIVE: We have previously shown that fetal and postnatal growth in heterozygous offspring of transgenic mice lacking an endothelial nitric oxide synthase (NOS3) depends on the parental source of the abnormal gene. Our objective in the current study was to differentiate between the roles of genetics and uterine environment in the fetal programming of growth. STUDY DESIGN: Homozygous NOS3 knockout (C57BL/6J-NOS3ÿ/ÿKO) and wild-type mice (NOS3+/+WT) were cross-bred to obtain 2 types of heterozygous embryos, maternally derived heterozygous (NOS3+/ÿmat) and paternally derived heterozygous (NOS3+/ÿpat). The NOS3+/ÿmat and NOS3+/ ÿpat embryos were harvested and transferred to the uteri of NOS3+/+WT foster mothers. The pups from each litter were counted and weighed on day 1, day 21 (weaning), and then weekly for 7 weeks (adult time). One-way ANOVA and Newman-Keuls post-hoc tests were used for statistical analysis (significance: P < 0.05). RESULTS: The number of pups was not different between the two groups. The weight gain from day 1 until weaning was similar between NOS3+/ÿmat and NOS3+/ÿpat in males and females. The weight then increased constantly in both groups until adult time. No significant differences were present between male and female. These data contrast with results in pups from natural pregnancies where weight was significantly decreased in the NOS3+/ÿmat (growing in abnormal uterine environment, i.e., NOS3ÿ/ÿKO) compared with NOS3+/ÿpat (growing in normal uterine environment, i.e., NOS3+/+WT). CONCLUSION: These data support a primary role for abnormal uterine environment, and not genetic imprinting, in the fetal programming of growth.
Volume 189, Number 6 Am J Obstet Gynecol 93
HYPERTENSION MANAGEMENT BASED ON HEMODYNAMIC MEASUREMENTS DAVID CHAFFIN1, 1Society for Maternal-Fetal Medicine, Huntington, WV OBJECTIVE: To evaluate the clinical outcomes of a program to pharmacologically manage hypertensive pregnant patients based on serial measurements of blood pressure, cardiac output (CO), and systemic vascular resistance (SVR) beginning in the second trimester. STUDY DESIGN: Patients were enrolled in the program based on a history of chronic hypertension, type 1 diabetes, chronic renal failure, or early severe preeclampsia. Blood pressure, cardiac output, and systemic vascular resistance were measured using thoracic electrical impedance plethysmography. Patients with hyperdynamic or mixed vasoconstrictive/hyperdynamic measurements at a gestational age of less than 24 weeks were treated with atenolol. Vasodilators were added for SVR >1100 dyne*sec*cmÿ5. Patients were followed on a regular basis until 34 weeks’ gestation with medication dosages adjusted to attempt to achieve normal hemodynamics. Patients were managed by referring physicians after 34 weeks. RESULTS: The first 106 patients treated with atenolol enrolled at less than 24 weeks are included in this report. The mean gestational age at enrollment was 16 ± 4 wks. The average mean arterial blood pressure was 99 ± 12 mm Hg. Initial cardiac output was 7.7 ± 1.5 liters/min (normal < 7.6 liters/min) with a range of 4.1 to 12.8 liters/min. Atenolol dosage ranged from 25 mg to 200 mg per day. Additional vasodilators used included hydralazine, nifedipine, and Isordil. Mean gestational age at delivery was 36 ± 3 weeks with a mean percentile birth weight of 47 (11% less than 10th centile). There were 4 patients delivered at less than 34 weeks for hypertensive complications. Three fetal deaths were due to premature labor at 22 to 23 weeks. 35 patients delivered between 34 and 37 weeks. The average hospital stay for these infants was 3.5 days (2.5 days for term infants). CONCLUSION: Early intervention with atenolol in an at-risk population with abnormal hemodynamics results in a low rate of early hypertensive complications with no increase in growth restriction.
95
ABNORMAL VASCULAR FUNCTION IN OFFSPRING OF ENDOTHELIAL NITRIC OXIDE SYNTHASE KNOCKOUT MICE: GENETIC FACTORS OR FETAL PROGRAMMING BY UTERINE ENVIRONMENT? MONICA LONGO1, JOSJE LANGENVELD2, YURI VEDERNIKOV1, GARLAND ANDERSON1, RADEK BUKOWSKI1, ROBERT GARFIELD1, GEORGE SAADE1, 1 University of Texas Medical Branch, Dept. of Obstetrics & Gynecology, Galveston, TX 2Maastricht University Medical Center, Dept. of Obstetrics & Gynecology, Maastricht, The Netherlands OBJECTIVE: We have previously shown that the abnormal vascular reactivity in heterozygous offspring of transgenic mice lacking an endothelial nitric oxide synthase (NOS3) is manifest only when the mother is knockout. Our objective was to determine whether genetic imprinting or abnormal uterine environment accounts for this fetal programming of vascular function. STUDY DESIGN: Homozygous NOS3 knockout (C57BL/6J-NOS3ÿ/ÿKO) and wild-type mice (NOS3+/+WT) were cross-bred to obtain 2 types of heterozygous embryos, maternally derived heterozygous (NOS3+/ÿmat) and paternally derived heterozygous (NOS3+/ÿpat). The NOS3+/ÿmat and NOS3+/ ÿpat embryos were harvested and transferred to the uteri of wild-type (NOS3+/ +WT ) foster mothers. Female and male mice from these litters were sacrificed at 78 weeks of age (n = 5-10/group) and 2-mm segments of carotid artery were mounted in a wire myograph to study vascular reactivity in vitro. Concentrationresponse curves to a1-adrenergic agonist phenylephrine (PE, 10ÿ10ÿ10ÿ5 M) and endothelium-dependent vasorelaxant acetylcholine (ACh, 10ÿ10ÿ10ÿ5 M) were obtained. The maximal effect, area under the concentration-response curve, and the EC50 (concentration producing 50% of the maximal effect) were calculated. Unpaired Student t-test and one-way ANOVA followed by NewmanKeuls post-hoc test were used for analysis (significance: P < 0.05). RESULTS: The vasorelaxant responses to ACh and the contractile responses to PE in later life were not significantly different in NOS3+/ÿmat and NOS3+/ÿpat female and male mice that developed in the uteri of genetically normal NOS3+/ +WT foster mothers. Transfer of heterozygous embryos into normal females abolished the previously reported effect of parental origin on vascular reactivity later in life. CONCLUSION: These data support the role of abnormal uterine environment rather than genetic imprinting in the fetal programming of abnormal vascular function in later life.
94
EFFECT OF PREGNANCY ON VASCULAR RESPONSES IN THE OFFSPRINGS OF ENDOTHELIAL NITRIC OXIDE SYNTHASE KNOCKOUT MICE MONICA LONGO1, JOSJE LANGENVELD2, VENU JAIN1, YURI VEDERNIKOV1, GARLAND ANDERSON1, GARY HANKINS1, ROBERT GARFIELD1, GEORGE SAADE1, 1University of Texas Medical Branch, Dept. of Obstetrics & Gynecology, Galveston, TX 2Maastricht University Medical Center, Dept. of Obstetrics & Gynecology, Maastricht, The Netherlands OBJECTIVE: Transgenic mice lacking the endothelial nitric oxide synthase (NOS3) have litters with growth deficiency and abnormal vascular reactivity in later life. The objective of the study was to evaluate the role of gravidity in modulating these responses. STUDY DESIGN: Litters from homozygous NOS3 knockout (C57BL/6JNOS3ÿ/ÿKO) and maternally derived heterozygous (NOS3+/ÿMat) mice were used. These litters were obtained from two groups of breeder mice: G1 (gravidity 0-2) and G2 (gravidity 5-9). Female mice from these litters (G1-NOS3ÿ/ÿKO, G1NOS3+/ÿMat, G2-NOS3ÿ/ÿKO, G2-NOS3+/ÿMat) were sacrificed at 7-8 weeks of age (n = 8-10/group) and 2-mm segments of carotid artery were mounted in a wire myograph for vascular reactivity study. Responses to phenylephrine (PE, 10ÿ10 to 10ÿ5 M) and acetylcholine (ACh, 10ÿ10 to 10ÿ5 M) were studied. The maximal effect (ME), area under the concentration-response curve, and the EC50 (concentration producing 50% of the maximal effect) were calculated. One-way ANOVA was used for statistical analysis (significance: P < 0.05). RESULTS: Ach produced vasorelaxation in a dose-dependent manner in G2-NOS3ÿ/ÿKO and G2-NOS3+/ÿMat, while ACh effects were completely abolished in the G1-NOS3ÿ/ÿKO and G1-NOS3+/ÿMat. PE contraction was significantly increased in G1-NOS3ÿ/ÿKO and G1-NOS3+/ÿMat compared with G2-NOS3ÿ/ÿKO and G2-NOS3+/ÿMat (ME: G1-NOS3ÿ/ÿKO, 178.3 ± 6.1 vs G2NOS3ÿ/ÿKO, 92 ± 8.8; G1-NOS3+/ÿMat, 210.7 ± 21.3 vs G2-NOS3+/ÿMat, 111 ± 6.6, P < 0.05). CONCLUSION: These data support the role of abnormal uterine environment in the fetal programming of vascular function in later life. The uterine environment in mice lacking a functional NOS improves with successive gestations, leading to improvement in vascular function in later life.
96
BIRTHWEIGHT AND POSTNATAL GROWTH IN OFFSPRING OF ENDOTHELIAL NITRIC OXIDE SYNTHASE KNOCKOUT MICE: GENETIC FACTORS OR FETAL PROGRAMMING BY UTERINE ENVIRONMENT? MONICA LONGO1, JOSJE LANGENVELD2, RADEK BUKOWSKI1, GARY HANKINS1, GARLAND ANDERSON1, ROBERT GARFIELD1, GEORGE SAADE1, 1University of Texas Medical Branch, Dept. of Obstetrics & Gynecology, Galveston, TX 2Maastricht University Medical Center, Dept. of Obstetrics & Gynecology, Maastricht, The Netherlands OBJECTIVE: We have previously shown that fetal and postnatal growth in heterozygous offspring of transgenic mice lacking an endothelial nitric oxide synthase (NOS3) depends on the parental source of the abnormal gene. Our objective in the current study was to differentiate between the roles of genetics and uterine environment in the fetal programming of growth. STUDY DESIGN: Homozygous NOS3 knockout (C57BL/6J-NOS3ÿ/ÿKO) and wild-type mice (NOS3+/+WT) were cross-bred to obtain 2 types of heterozygous embryos, maternally derived heterozygous (NOS3+/ÿmat) and paternally derived heterozygous (NOS3+/ÿpat). The NOS3+/ÿmat and NOS3+/ ÿpat embryos were harvested and transferred to the uteri of NOS3+/+WT foster mothers. The pups from each litter were counted and weighed on day 1, day 21 (weaning), and then weekly for 7 weeks (adult time). One-way ANOVA and Newman-Keuls post-hoc tests were used for statistical analysis (significance: P < 0.05). RESULTS: The number of pups was not different between the two groups. The weight gain from day 1 until weaning was similar between NOS3+/ÿmat and NOS3+/ÿpat in males and females. The weight then increased constantly in both groups until adult time. No significant differences were present between male and female. These data contrast with results in pups from natural pregnancies where weight was significantly decreased in the NOS3+/ÿmat (growing in abnormal uterine environment, i.e., NOS3ÿ/ÿKO) compared with NOS3+/ÿpat (growing in normal uterine environment, i.e., NOS3+/+WT). CONCLUSION: These data support a primary role for abnormal uterine environment, and not genetic imprinting, in the fetal programming of growth.