Maternal Cardiovascular Adaptation Research Articles

Spiral Arterial Remodeling Is Not Essential for Normal Blood Pressure Regulation in Pregnant Mice

Maternal cardiovascular adaptations occur in normal pregnancy, systemically, and within the uterus. In humans, gestational control of blood pressure is clinically important. Transient structural remodeling of endometrial spiral arteries normally occurs in human and mouse pregnancies. In mice, this depends on uterine natural killer cell function. Using normal and immune-deficient mice, we asked whether spiral artery remodeling critically regulates gestational mean arterial pressure and/or placental growth. Radiotelemetric transmitters were implanted in females and hemodynamic profiles to a dietary salt challenge and to pregnancy were assessed. Implantation sites from noninstrumented females were used for histological morphometry. Both normal and immune-deficient mice had normal sensitivity to salt and showed similar 5-phase gestational patterns of mean arterial pressure correlating with stages of placental development, regardless of spiral artery modification. After implantation, mean arterial pressure declined during the preplacental phase to reach a midgestation nadir. With gestation day 9 opening of placental circulation, pressure rose, reaching baseline before parturition, whereas heart rate dropped. Heart rate stabilized before parturition. Placental sizes deviated during late gestation when growth stopped in normal mice but continued in immune-deficient mice. As an indication of the potential for abnormal hemodynamics, 2 pregnant females delivering dead offspring developed late gestational hypertension. This study characterizes a dynamic pattern of blood pressure over mouse pregnancy that parallels human gestation. Unexpectedly, these data reveal that spiral artery remodeling is not required for normal gestational control of blood pressure or for normal placental growth.

Maternal arterial stiffness in pregnancies affected by preeclampsia

Preeclampsia (PE) is characterized by an aberrant maternal cardiovascular adaptation to pregnancy and increased cardiovascular risk later on in life. The aim of this study was to compare the maternal wave reflections and arterial stiffness in women with established PE and those with normotensive pregnancies, after systematic adjustment for known confounders. This was a cross-sectional study involving 69 normotensive, pregnant women and 54 women with established PE. Maternal wave reflection (augmentation index) and pulse wave velocity of the carotid-radial and carotid-femoral parts of the arterial tree were assessed noninvasively using applanation tonometry. The measurements were adjusted for maternal age, heart rate, mean arterial pressure, and aortic time to wave reflection and expressed as multiples of the median (MoM) of the control group. In the PE group, compared with controls, there was an increase in the median pulse wave velocity of both the carotid to femoral [1.1, interquartile rage (IQR) 1.0-1.3 MoM vs. 0.9, IQR 0.9-1.0 MoM; P < 0.0001] and carotid to radial (1.0, IQR 0.9-1.1 MoM vs. 0.9, IQR 0.9-1.0 MoM; P = 0.01) parts of the arterial tree. In contrast, there were no significant differences between the two groups in the median augmentation index (0.9, IQR 0.7-1.1 MoM vs. 1.0, IQR 0.5-1.8 MoM; P = 0.46). In conclusion, we found that established PE is characterized by increased maternal arterial stiffness but not altered maternal wave reflection.

A Longitudinal Study of the Maternal Cardiovascular Adaptation to Spontaneous and Assisted Conception Pregnancies

Objective: To determine the sequence and extent of maternal cardiovascular adaptation in an integrated way in spontaneous and assisted conception pregnancies Methods: Cardiovascular assessments were performed pre-pregnancy, during pregnancy and 6 weeks post delivery in women with normal spontaneously conceived singleton pregnancies (n = 13); singleton IVF pregnancies (n = 5); singleton OD pregnancies (n = 4); and multiple pregnancies (n = 6). Results: The OD singleton pregnancies had a significantly higher diastolic and mean blood pressure (BP) than the normal singleton pregnancies at 10 weeks gestation (p = 0.010 and 0.008, respectively), and the multiple pregnancy group had a higher systolic and mean BP at 16 weeks gestation than the IVF singleton pregnancy group (p = 0.045 and 0.033, respectively). The multiple pregnancy group had higher heart rate (HR) at 16 weeks gestation (p = 0.010), higher fractional shortening (FS) at 16 weeks gestation (p = 0.006), and higher left ventricular (LV) mass at 26 weeks gestation (p = 0.049) than the IVF singleton pregnancy group. The rate of change of LV mass was correlated to the rate of change of the blood pressure (r = 0.725, p = 0.005 for mean BP) and inversely correlated to the rate of change of fractional shortening (r = 0.767, and p = 0.002). Conclusion: Ovum donation pregnancies are associated with higher BP in early pregnancy, whilst multiple pregnancies are associated with higher BP, FS and LV mass in later pregnancy.

Haemodynamic changes in the second half of pregnancy: a longitudinal, noninvasive study with thoracic electrical bioimpedance

Maternal cardiovascular adaptations to pregnancy are necessary for an adequate fetomaternal circulation. However, the time course of physiological haemodynamic changes during the second half of pregnancy remains unclear. Various methods, invasive and noninvasive, are described to measure these changes. The thoracic electrical bioimpedance (TEB) technique is a method which is especially suitable to measure haemodynamic changes over time. The aim of the study was to determine both individual and group trends of haemodynamic changes in healthy pregnant women during the second half of pregnancy by means of TEB. Outcome variables are heart rate (HR), stroke volume (SV), cardiac output (CO) and blood pressure. Longitudinal study. Outpatient antenatal care clinic of university hospital. A total of 22 healthy nonsmoking women with an uncomplicated singleton pregnancy and without pre-existing vascular disorders were invited. TEB and blood pressure measurements were performed at each regular visit from about 24 weeks of gestation through term age. Trends were calculated with the random effects model. Data obtained from 19 women were analysed, with a median of eight (range 3-11) measurements. HR showed a linear increase (P < 0.0005) and a quadratic trend (P < 0.0005). SV decreased linearly (P = 0.046), without a quadratic course. CO remained stable over time. During the second half of physiological pregnancy, significant trends could be determined. An increase in HR, a decrease in SV, a stable CO and an increase in systolic and diastolic blood pressures were found.

Endothelial progenitor cells and preeclampsia

The maternal cardiovascular adaptation to pregnancy involves a complex physiologic response to the presence of the growing conceptus, including alterations in maternal vascular endothelial cells that contribute to a profound fall in total systemic vascular resistance. There is a large body of evidence that adverse changes in the vascular endothelium underlie the multisystemic maternal manifestations of preeclampsia. Our knowledge is incomplete regarding the mechanisms of adaptive endothelial changes of normal pregnancy and why these changes are attenuated or fail in women who develop preeclampsia. Populations of bone-marrow derived endothelial progenitor cells (EPCs) exist in the adult that are mobilized into the circulation by stimuli such as estrogen and vascular endothelial growth factor. These EPCs can then differentiate into endothelial cells lining the lumen of blood vessels and/or release growth factors that act in a paracrine fashion to support the endothelium. EPCs are thus thought to function as a cellular reservoir to replace dysfunctional or senescent endothelial cells, and therefore may be critical to the overall health of the vascular endothelium. Data are emerging to suggest that the number of EPCs in the maternal circulation increases with normal pregnancy and that this change fails to occur in women with preeclampsia. While speculative at this point, our overall hypothesis is that an excess of antiangiogenic factors [such as the soluble receptors, soluble fms-like tyrosine kinase (sFlt-1) and soluble endoglin] interfere with nitric oxide-driven mobilization or activity of EPCs in the maternal circulation, contributing to the widespread endothelial dysfunction underlying the clinical manifestations of preeclampsia.

Folate Supplementation During Pregnancy Improves Offspring Cardiovascular Dysfunction Induced by Protein Restriction

Dietary protein restriction in the rat compromises the maternal cardiovascular adaptations to pregnancy and leads to raised blood pressure and endothelial dysfunction in the offspring. In this study we have hypothesized that dietary folate supplementation of the low-protein diet will improve maternal vascular function and also restore offspring cardiovascular function. Pregnant Wistar rats were fed either a control (18% casein) or protein-restricted (9% casein) diet +/-5 mg/kg folate supplement. Function of isolated maternal uterine artery and small mesenteric arteries from adult male offspring was assessed, systolic blood pressure recorded, and offspring thoracic aorta levels of endothelial nitric oxide (NO) synthase mRNA measured. In the uterine artery of late pregnancy dams, vasodilatation to vascular endothelial growth factor was attenuated in the protein-restricted group but restored with folate supplementation, as was isoprenaline-induced vasodilatation (P<0.05). In male offspring, protein restriction during pregnancy led to raised systolic blood pressure (P<0.01), impaired acetylcholine-induced vasodilatation (P<0.01), and reduced levels of endothelial NO synthase mRNA (P<0.05). Maternal folate supplementation during pregnancy prevented this elevated systolic blood pressure associated with a protein restriction diet. With folate supplementation, endothelium-dependent vasodilatation and endothelial NO synthase mRNA levels were not significantly different from either the control or protein-restricted groups. Maternal folate supplementation of the control diet had no effect on blood pressure or vasodilatation. This study supports the hypothesis that folate status in pregnancy can influence fetal development and, thus, the risks of cardiovascular disease in the next generation. The concept of developmental origins of adult disease focuses predominately on fetal life but must also include a role for maternal cardiovascular function.

Physiologic Cardiac Hypertrophy During Pregnancy Involves a Change in Gene Expression Regulating Cardiac Metabolism

Pregnancy is a chronic volume-overload state that necessitates maternal cardiovascular adaptations in order to support fetal development. Conscious dogs were studied using echocardiography before (Control), 60 days (60D) of pregnancy, and ~14 days post partum (PP). The Left Ventricular (LV) end-diastolic diameter, LV end-diastolic volume, heart rate, stroke volume, and cardiac output were significantly elevated at 60D vs. control (9%, 11%, 27%, 12% and 40% respectively, all p<0.05), and returned to normal levels PP. LV free wall mass was significantly larger in hearts at 60D (21% increase, p<0.05), indicating ventricular hypertrophy. We examined the changes in gene expression at those time points via the Affymetrix GeneChip® Canine Genome Array. We found elevated mRNA levels of genes that were indicative of cardiac hypertrophy, i.e.: MHC class II DLA beta chain; Microtubule-associated protein 1B; cardiac ankyrin repeat protein, metalloproteinase 9; myomegalin (80%, 61%, 60%, 52%, and 50% respectively, all p<0.05). Genes responsible for myocyte calcium signaling; sarcoplasmic reticulum Ca2+-transport ATPase; and cardiac ryanodine receptor 2 were significantly elevated (100%, and 60% respectively, p<0.05). Genes associated with glucose and glycogen metabolism such as; glycogen phosphorylase; pyruvate dehydrogenase; 6-phosphofructokinase were down regulated (−1.7, −1.6, −1.6 Fold change respectively, all p<0.05). Genes involved in free fatty acid oxidation such as isocitrate dehydrogenase; 3-ketoacyl-CoA thiolase; acetyl-coenzyme A synthetase (1.6, 1.6, 1.5 Fold change respectively, all p<0.05) among others were elevated. This indicates that during normal pregnancy the heart adapts by hypertrophy, increasing calcium signaling (inotropic state) and emphasizing FFA metabolism over glucose metabolism.

Emerging role of relaxin in renal and cardiovascular function.

Although traditionally associated with reproductive processes, relaxin is emerging as an important player in renal and cardiovascular function. Much of our recently acquired understanding of relaxin in this new context has arisen from studies of maternal renal and cardiovascular adaptations to pregnancy in rats where the hormone is turning out to be an important mediator. First, we highlight the influence of relaxin on renal hemodynamics and glomerular filtration rate, as well as on other peripheral circulations. Second, we discuss the effect of relaxin on both the steady and pulsatile systemic arterial load, as well as on the heart, in particular, coronary blood flow. Third, we consider the impact of the hormone on cultured endothelial and vascular smooth muscle cells. Fourth, we address the interaction of relaxin with renal and cardiac disease, as well as its role in angiogenesis. Finally, in Perspectives, we point out several key research questions in need of investigation that relate to a potential autocrine/paracrine role of relaxin in renal and cardiovascular tissues. Furthermore, on the basis of its potent vasodilatory and matrix-degrading attributes, we speculate about the therapeutic potential of relaxin in renal and cardiovascular diseases.

Uterine blood flow—a determinant of fetal growth

An adequate increase of uterine blood flow throughout gestation is essential for uterine, placental and fetal growth. Maternal cardiovascular adaptation has to provide the uterine perfusion that is necessary to meet the requirements of the developing and growing fetus by providing transport of nutrients and oxygen to the placenta and the fetus. Thus, uterine blood flow is inextricably linked to fetal growth and survival. Reductions of uterine blood flow can occur under acute or chronic conditions or in a combination of both. Chronic reductions of uterine blood flow can be observed in pregnancy-induced hyertension (PIH), diabetes mellitus in pregnancy and intrauterine growth restriction (IUGR). Chronic restrictions in uterine blood flow will elicit a placental and fetal response in the form of growth adaptation to the reduced supply of oxygen and nutrients to the conceptus. If compensatory growth restriction reaches its limits intrauterine fetal distress can ensue. Among the great number of experimental models of intrauterine growth restriction, those involving a generalized reduction in the uteroplacental blood supply are of significance to questions relating to human pregnancy. Despite physiological differences, particularly with regard to maternal metabolism and placentation, the occlusion model in the pregnant sheep is suitable for investigating questions about fetal and placental growth.

The genetics of pre-eclampsia: a feto-placental or maternal problem?

Pre-eclampsia is a potentially life-threatening disease of women during pregnancy leading to hypertension and proteinuria. It affects 1 in 15 pregnancies but, despite intense research efforts, the cause of the disease remains mysterious. Because pre-eclampsia only occurs during pregnancy and its symptoms resolve after delivery, factors from the placenta are thought to be involved. The role of the placenta could be production of 'abnormal' factors that initiate widespread inflammation and vaso-constriction. Alternatively, because the placenta normally contributes to maternal cardiovascular adaptations of pregnancy, it may be that normal placental functions fail in pre-eclampsia or that susceptibilities in the mother to hypertensive, vascular and/or renal disease prevent the appropriate normal responses to them. The potential contributions of both maternal and fetal genes to the onset of the disease have complicated the genetic analysis of the disease in humans. Recent studies have identified strains of transgenic and mutant mice that develop the hallmark features of pre-eclampsia-like disease - gestational hypertension, proteinuria and kidney lesions (glomerulosclerosis). Comparison of three different mouse models suggests that pre-eclampsia can be initiated by at least three independent mechanisms: pre-existing borderline maternal hypertension that is exacerbated by pregnancy (BPH/5 strain of mice), elevated levels of the vasoconstrictor angiotensin II in the maternal circulation by placental over-production of renin (renin/angiotensinogen transgenic mice), and placental pathology (p57Kip2 mutant mice). These findings imply that the pathogenesis of pre-eclampsia cannot be explained by a single mechanism. Therefore, segregation of the human disease into different subtypes may be a key first step in identifying genetic risk factors.

Endogenous estrogen mediates vascular reactivity and distensibility in pregnant rat mesenteric arteries.

The role of estrogen in the maternal systemic cardiovascular adaptations during pregnancy is still controversial. Female Sprague-Dawley rats were implanted at day 14 of pregnancy with either a 50-mg tamoxifen pellet (estrogen receptor blocker, n = 10) or placebo pellet (n = 10). Virgin female rats were a nonpregnant control (n = 7). At days 20-22 of pregnancy, resistance-sized mesenteric arteries were mounted onto a dual-chamber arteriograph system. Pregnancy significantly blunted the pressor response to phenylephrine [measurement of the effective concentration that yielded 50% maximum response (EC(50)) values were 1.5 +/- 0.22 vs. 0.69 +/- 0.16 microM (P < 0.05)] and enhanced vasodilation to ACh [EC(50) = 1.13 +/- 2.53 vs. 3.13 +/- 6.04 nM (P < 0.05)] compared with nonpregnant rats. However, tamoxifen treatment during pregnancy reversed these effects. Inhibition of nitric oxide (NO) synthase with N(G)-monomethyl-L-arginine (250 microM) shifted only the responses of the placebo-treated pregnant group to both phenylephrine and ACh. Arterial distensibility in the placebo-treated pregnant group was also significantly increased (P < 0.05) compared with nonpregnant and tamoxifen-treated pregnant animals. In summary, endogenous estrogen during pregnancy increases NO-dependent modulation of vessel tone and arterial distensibility.

Plasma adrenomedullin levels in pregnancies with appropriate for gestational age and small for gestational age infants.

To evaluate whether maternal and fetal plasma adrenomedullin levels in pregnancies with small for gestational age (SGA) infants are different from those in pregnancies with appropriate for gestational age (AGA) infants. Maternal and fetal circulating adrenomedullin levels were compared between 62 pregnancies with AGA (43 delivered vaginally and 19 delivered by elective cesarean section) and 28 pregnancies with SGA (20 delivered vaginally and 8 delivered by elective cesarean section) at birth. Plasma adrenomedullin levels were measured from maternal and cord venous blood samples using a radioimmunoassay. Umbilical artery blood pH was also measured. There were no significant differences for maternal total adrenomedullin levels, mature adrenomedullin levels, and its ratio among the groups. There were also no significant differences for fetal total adrenomedullin levels, mature adrenomedullin levels, and its ratio among the groups. In the AGA group delivered vaginally, fetal mature/total adrenomedullin ratio (mean +/- standard error, 16.6 +/- 0.7%) was significantly higher than the maternal ratio (13.8 +/- 0.6%) (p < 0.05). In the SGA group delivered vaginally, fetal mature/total adrenomedullin ratio (18.5 +/- 1.0%) was also significantly higher than the maternal ratio (14.5 +/- 0.6%) (p < 0.05). There was no significant difference in umbilical artery blood pH among the groups. These results suggest that maternal and fetal plasma circulating adrenomedullin levels may play a role in maternal and fetal cardiovascular adaptation during delivery in pregnancies with both AGA and SGA infants.

Uterine perfusion and fetal growth

An adequate increase of uterine blood flow throughout gestation is essential for uterine, placental and fetal growth. Maternal cardiovascular adaptation has to provide the uterine perfusion that is necessary to meet the requirements of the developing and growing fetus by providing transport of nutrients and oxygen to the placenta and the fetus. Thus uterine blood flow is inextricably linked to fetal growth and survival. Reductions of uterine blood flow can occur under acute or chronic conditions or in a combination of both. Chronic reductions of uterine blood flow can be observed in pregnancy induced hyertension (PIH), diabetes mellitus in pregnancy and intrauterine growth restriction (IUGR). Chronic restrictions in uterine blood flow will elicit a placental and fetal response in the form of growth adaptation to the reduced supply of oxygen and nutrients to the conceptus. If compensatory growth restriction reaches its limits intrauterine fetal distress can ensue.

THE PARTURIENT WITH CARDIAC DISEASE

The presence of significant cardiac or cardiovascular disease has traditionally been one of the great contraindications to pregnancy. The second half of the twentieth century has been witness to an explosion of advances in medical and surgical technology as well as in the management of routine medical and surgical conditions. Obstetric patients have been beneficiaries of such achievements; maternal mortality from cardiovascular causes has declined progressively since the 1950s (Fig. 1) . 32 , 42 , 75 Maternal mortality in the 1990s is less than 1% in women with mild to moderate cardiac disease. The reasons for this decrease are multifactorial: (1) the decrease in rheumatic heart disease seen with the advent of antibiotics, (2) the availability of surgical correction for many serious congenital and acquired cardiac diseases, and (3) improved medical therapy for arrhythmias, heart failure, etc. The mortality rate for pregnant women with more severe cardiac pathology (New York Heart Association [NYHA] class III–IV) is higher and reported to be 5% to 15%, and fetal mortality approaches 30% in this population of women. 17 , 27 , 33 , 37 Women with congenital heart disease, collagen vascular conditions, and rheumatic fever—historically the leading causes of cardiac disease in pregnant women 7 , 42 , 51 , 75 —now generally receive appropriate and often curative therapy early enough in the course of their disease to prevent the development of irreversible sequelae. Many more of these patients now survive to child-bearing age. The medical literature is replete with case reports and clinical investigations attesting to the success of strategies for the reduction of maternal morbidity and mortality in women with preconceptual cardiac lesions. With all of the clinical successes, it is important to note that family planning and pre-pregnancy counseling, so as to avoid pregnancy, is often appropriate for those with more severe diseases such as pulmonary hypertension, coarctation of the aorta with involvement of the aortic root, and Marfan's disease with aortic root widening. 1 , 6 , 32 , 65 The obstetrician coordinates a multidisciplinary team of health-care professionals—the anesthesiologist, cardiologist, neonatologist, and nursing staff—who help guide the gravidae with cardiac disease toward a successful perinatal outcome. Some undesired outcomes may not be preventable, as this population of patients, especially those with cyanotic congenital heart defects, experience a greater incidence of spontaneous abortion, intrauterine growth retardation and fetal demise, and preterm labor and delivery; moreover, these women have an increased chance of producing offspring with similar congenital heart defects. 60 , 66 The task of the anesthesiologist caring for the pregnant cardiac patient is made more problematic by the fact that many cardiac lesions worsen during gestation as maternal cardiovascular adaptations to pregnancy place progressively greater stresses on the heart. It is possible for a woman to deteriorate from NYHA class I or II to class III or IV (Table 1) as her physiology undergoes the changes to support the growth, development, and delivery of her baby; up to 40% of women with only mild preconceptual cardiac disease can expect to suffer some degree of cardiac compromise during the course of pregnancy despite aggressive management by the health-care team. 17

A longitudinal study of maternal serum vascular endothelial growth factor in early pregnancy.

Using a competitive radioimmunoassay to measure total immunoreactive vascular endothelial growth factor (VEGF), we describe for the first time longitudinal changes in serum VEGF in early pregnancy. The measurements were obtained from 26 women following the transfer of cryopreserved embryos; 18 singleton and eight twin pregnancies were identified by ultrasound at 6 weeks gestation and subsequently delivered as live births. Subjects did not have corpora lutea and exogenous hormone support was provided for the first 70 days of pregnancy. Serum VEGF increased approximately 30 days after embryo transfer and thereafter continued to rise in both singleton and twin pregnancies over a period of 20-40 days after which concentrations remained elevated. The longitudinal profile of serum VEGF concentrations was characterized by a logistic curve for singleton and twin pregnancies; the profile of VEGF concentrations in the twin pregnancies was significantly higher than in the singleton pregnancies (P < 0.0001). Profiles of the longitudinal concentrations of serum human chorionic gonadotrophin (HCG), oestradiol and progesterone were created by polynomial regression for singleton and twin pregnancies. The VEGF profiles were positively correlated with the profiles of HCG (r = 0.44, P = 0.02) and oestradiol (r = 0.36, P = 0.07) but not progesterone (r = 0.16, P = 0.42). Serum VEGF concentrations in the singleton thawed embryo pregnancies were compared with gestation-matched normal singleton pregnancies with corpora lutea. Concentrations of VEGF were significantly (P = 0.004) greater in the pregnancies with corpora lutea although this difference became less marked with advancing gestation. In addition to its important role in angiogenesis, we speculate that VEGF is involved in mechanisms which control the maternal cardiovascular adaptation to pregnancy.

Maternal serum vascular endothelial growth factor during early pregnancy.

1. The objectives of the study were: (i) to investigate the serum concentrations of vascular endothelial growth factor (VEGF) in pregnant and non-pregnant women; and (ii) to study the relationship between the levels of maternal serum VEGF and the serum concentrations of human chorionic gonadotrophin (hCG) and progesterone during the first trimester. 2. Total immunoreactive VEGF was measured by competitive RIA using recombinant human VEGF165 and a polyclonal antiserum. Serum VEGF was measured in 60 non-pregnant women of childbearing age. These data were compared with serum VEGF measured in 363 women between 41 and 91 days of gestation. 3. The median serum VEGF concentration was 1.10 micrograms/l (interquartile range 0.91-1.30) in the nonpregnant women and 2.13 micrograms/l (interquartile range 1.62-2.77) in the pregnant women. Serum levels of VEGF were significantly higher among the pregnant cohort (P < 0.0001). Serum VEGF concentration was positively correlated with gestational age, increasing until ten completed weeks of pregnancy. Serum VEGF was negatively correlated with maternal height and weight, and positively correlated with serum hCG and serum progesterone (P < or = 0.0001 in all cases). Serum VEGF was lower in the pregnant women who smoked (P = 0.06). 4. Our data show a positive and highly significant correlation between maternal serum levels of VEGF and hormones reflecting placental function (hCG, progesterone). We speculate that VEGF production is increased by progesterone and hCG, and that VEGF has a positive influence on trophoblast development. VEGF may also be involved in the initiation of the maternal cardiovascular adaptation to pregnancy.

Severely impaired fetal growth is preceded by maternal hemodynamic maladaptation in very early pregnancy.

To test the hypothesis that in pregnancies complicated by intrauterine growth retardation (IUGR) maternal cardiovascular adaptation is already abnormal in the first weeks of pregnancy. University Hospital Maastricht, Maastricht, The Netherlands. Fourteen healthy pregnant women, recruited from the subfertility clinic. Ten pregnancies were uneventful and four pregnancies resulted in the birth of growth retarded infants. Maternal cardiovascular status was followed longitudinally by combined M-mode and Doppler echocardiography. Studies were performed weekly between the fifth and 10th week, at 14, 25 and 35 weeks and postpartum. Differences between the two groups were analyzed by nonparametric tests. In early pregnancy, the IUGR group differed from the normal group by a consistently smaller left atrial diameter and a cardiac output that failed to increase. Postpartum the subjects in the IUGR group had a significantly smaller left atrial diameter and faster mean circumferential fiber shortening. Maternal hemodynamic adaptation in the first weeks of pregnancy is defective in IUGR pregnancies, presumably associated with a concomitant inadequacy of the vascular filling state.

Maternal cardiovascular hemodynamic adaptation to pregnancy.

Maternal cardiovascular adaptation to pregnancy involves enormous changes. Cardiac output increases in early pregnancy, initially as a result of an increased heart rate, soon followed by an increased stroke volume. Cardiac output continues to increase until midpregnancy, and remains stable afterward, with a possible small decline in the last weeks of pregnancy. Blood pressure decreases in early pregnancy, reaching a minimum in midpregnancy, then returning to baseline levels at term. Consequently, peripheral vascular resistance is reduced throughout pregnancy. Myocardial contractility seems to be increased during all trimesters of pregnancy, thus gradually provoking the development of a mild ventricular hypertrophy. The increase in preload, which develops in concert with the increment in blood volume, leads to an increase in left atrial diameter, which also begins during early pregnancy. During labor, both cardiac output and blood pressure increase. After delivery, cardiac output initially increases, but begins to decrease within the first hour to reach baseline levels 2 weeks postpartum. Most cardiovascular parameters show their greatest changes within 2 weeks postpartum. Five months postnatally, only a mild residual ventricular hypertrophy persists.

Effect of atrial natriuretic peptide and other vasoactive compounds on the uterine vascular bed of the nonpregnant sheep.

It has been reported that atrial natriuretic peptide (ANP) concentrations are elevated in pregnancy and further elevated in pregnancy-induced hypertension. Atrial stretch and volume expansion appear to be important stimuli for ANP release. During normal pregnancy, a striking change in hemodynamics occurs that may increase plasma ANP concentrations. ANP has potent natriuretic, diuretic, and smooth muscle relaxant activities. The biological effects of ANP during pregnancy may play an important role in the physiology and pathophysiology of pregnancy. Because of possible interactions during pregnancy due to secondary effects of maternal cardiovascular changes and physiological adaptation, the present study sought to evaluate and characterize the local effects of atriopeptin II on the uterine vascular bed of the nonpregnant sheep. Ewes with catheters in the femoral artery, femoral vein, and uterine artery and electromagnetic flow probes on the middle uterine arteries were monitored for blood pressure (BP), heart rate (HR), and uterine blood flow before and after the administration into the uterine artery of bolus injections of 2, 4, 20, and 40 x 10(-9) M (5, 10, 50, and 100 micrograms) of the synthetic ANP (atriopeptin II). For comparison purposes, the effects of prostaglandin I2 in doses of 1.2, 2.5, 12, and 25 x 10(-8) M (5, 10, 50, and 100 micrograms), vasoactive intestinal polypeptide in doses of 3, 9, 30, 90, 300, and 900 x 10(-11) M (0.1, 0.3, 1, 3, 10, and 30 micrograms), and bradykinin in doses of 9.4, 28, 94, 280, 940, and 2800 x 10(-11) M (0.1, 0.3, 1, 3, 10, and 30 micrograms) were also tested. Appropriate vehicles were tested and found to be without effect. All four compounds were found to be vasodilators of the nonpregnant uterine vasculature. ANP administered into the uterine artery decreased BP (87 +/- 4 mm Hg to 79 +/- 4 mm Hg with 50 micrograms [20 x 10(-9) M]), increased HR (90 +/- 5 bpm to 105 +/- 4 bpm), and significantly increased uterine blood flow (from 14 +/- 3 to 37 +/- 4 ml/min with a dose of 100 micrograms [40 x 10(-8) M, P < 0.05]). Prostaglandin I2 failed to alter BP, but caused significant increases on HR (100 +/- 4 to 124 +/- 13 bpm, P < 0.05) and uterine blood flow (17 +/- 4 to 73 +/- 10 ml/min, P < 0.05). Vasoactive intestinal polypeptide caused a significant tachycardia (97 +/- 10 to 158 +/- 9 bpm, P < 0.05) at the highest dose.(ABSTRACT TRUNCATED AT 400 WORDS)

Maternale kardiovaskuläre Adaptation während der Schwangerschaft*

Maternal cardiovascular adaptations during pregnancy, such as cardiac output, blood volume, hormones, water and electrolyte balance, arterial blood pressure, vascular resistance, uterine blood flow amongst others ensure the well-being of the mother and of the fetus. Several of these changes are not yet well understood. This report reviews the factual changes in cardiovascular physiology during pregnancy. Methodological experimental problems are identified and their relationship to the interpretation of the data discussed. Open scientific questions are identified and the experimental designs necessary to answer them are discussed. The possible mechanisms which are responsible for these changes are addressed. Special attention is given to arterial blood pressure during pregnancy as the regulated variable. It is shown how cardiovascular parameters are involved in the regulation of blood pressure and the signals, which trigger these changes. The effects of the vasoactive agents, angiotensin II and catecholamines, on the circulation during pregnancy are reviewed. Alterations of baroreceptor function are discussed for this time period. Further investigations should assess venous function during pregnancy to elucidate mechanisms by which such maternal adaptations occur.