How I treat thrombotic thrombocytopenic purpura in pregnancy.

Thrombotic thrombocytopenic purpura (TTP) is an acute, life-threatening thrombotic microangiopathy (TMA) caused by acquired or congenital severe deficiency of ADAMTS13. Pregnancy is a recognized risk factor for precipitating acute (first or recurrent) episodes of TTP. Differential diagnosis with other TMAs is particularly difficult when the first TTP event occurs during pregnancy; a high index of suspicion and prompt recognition of TTP are essential for achieving a good maternal and fetal outcome. An accurate distinction between congenital and acquired cases of pregnancy-related TTP is mandatory for safe subsequent pregnancy planning. In this article, we summarize the current knowledge on pregnancy-associated TTP and describe how we manage TTP during pregnancy in our clinical practice.

The role of oxytocin and vasopressin in the pathophysiology of heart failure in pregnancy and in fetal and neonatal life.

Pregnancy and early life create specific psychosomatic challenges for the mother and child, such as changes in hemodynamics, resetting of the water-electrolyte balance, hypoxia, pain, and stress, that all play an important role in the regulation of the release of oxytocin and vasopressin. Both of these hormones regulate the water-electrolyte balance and cardiovascular functions, maturation of the cardiovascular system, and cardiovascular responses to stress. These aspects may be of particular importance in a state of emergency, such as hypertension in the mother or severe heart failure in the child. In this review, we draw attention to a broad spectrum of actions exerted by oxytocin and vasopressin in the pregnant mother and the offspring during early life. To this end, we discuss the following topics: 1) regulation of the secretion of oxytocin and vasopressin and expression of their receptors in the pregnant mother and child, 2) direct and indirect effects of oxytocin and vasopressin on the cardiovascular system in the healthy mother and fetus, and 3) positive and negative consequences of altered secretion of oxytocin and vasopressin in the mother with cardiovascular pathology and in the progeny with heart failure. The present survey provides evidence that moderate stimulation of the oxytocin and vasopressin receptors plays a beneficial role in the healthy pregnant mother and fetus; however, under pathophysiological conditions the inappropriate action of these hormones exerts several negative effects on the cardiovascular system of the mother and progeny and may potentially contribute to the pathophysiology of heart failure in early life.

ß1 adrenoceptor antibodies induce myocardial apoptosis via inhibiting PGC-1α-related pathway.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is life-threatening heart disease. However, the causes and pathogenesis of PPCM remain unclear. Previous studies found that ß1 adrenoceptor antibodies (ß1AA) had possible involvement in the development of PPCM. In the present study, we determined the potential relationship between PPCM and ß1AA, including the mechanism of ß1AA leading to PPCM. METHODS: We extracted the ß1AA from the postpartum Wistar rats that were injected by the antigen peptide segment of the ß1 adrenoceptor to produce PPCM. We tested the effects of ß1AA on H9C2 cell line by CCK-8, LDH, TUNEL, SA-ELISA, qRT-PCR, and western blot methods. Furthermore, PGC-1α was overexpressed to rescue the effect of ß1AA on H9C2 cells. RESULTS: We found that the extracted ß1AA induced apoptosis of cardiac myocytes of H9C2 cell line. Moreover, the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), which is a master regulator of mitochondrial metabolism, and its downstream transcript vascular endothelial growth factor (VEGF) got decreased in H9C2 cells after ß1AA treatment. In addition, the effect of ß1AA could be inhibited by atenolol, the antagonist of ß1 adrenoceptors (ß1AR) and imitated by isoprenaline, the agonist of ß1AR. Furthermore, overexpression of PGC-1α in the H9C2 cells rescued the apoptosis of cells and inhibitory expression of VEGF induced by ß1AA. CONCLUSIONS: Our results suggest that the symptoms of PPCM due to myocardial cell apoptosis induced by ß1AA inhibiting the PGC-1α-related pathway impairs mitochondrial energy metabolism. Therefore, our results uncover a previously unknown role of the ß1AA pathway in the etiology of PPCM and provide a novel potential target for the treatment of PPCM.

Association of Spontaneous Preterm Delivery and Future Maternal Cardiovascular Disease.

Cardiovascular disease (CVD) risk factors are well established. However, little is known about a woman's cardiovascular response to pregnancy, which appears to be an early marker of future maternal CVD risk. Spontaneous preterm delivery (sPTD) has been associated with a ≤3-fold increased risk of maternal CVD death later in life compared with having a term delivery. This review focuses on 3 key areas to critically assess the association of sPTD and future maternal CVD risk: (1) CVD risk factors, (2) inflammatory biomarkers of interest, and (3) specific forms of vascular dysfunction, such as endothelial function and arterial stiffness, and mechanisms by which each may be linked to sPTD. The association of sPTD with subsequent future maternal CVD risk suggests that a woman's abnormal response to pregnancy may serve as her first physiological stress test. These findings suggest that future research is needed to understand why women with sPTD may be at risk for CVD to implement effective interventions earlier in a woman's life.

The DiPEP study: an observational study of the diagnostic accuracy of clinical assessment, D-dimer and chest x-ray for suspected pulmonary embolism in pregnancy and postpartum.

OBJECTIVE: To identify clinical features associated with pulmonary embolism (PE) diagnosis and determine the accuracy of decision rules and D-dimer for diagnosing suspected PE in pregnant/postpartum women DESIGN: Observational cohort study augmented with additional cases. SETTING: Emergency departments and maternity units at eleven prospectively recruiting sites and maternity units in the United Kingdom Obstetric Surveillance System (UKOSS) POPULATION: 324 pregnant/postpartum women with suspected PE and 198 pregnant/postpartum women with diagnosed PE METHODS: We recorded clinical features, elements of clinical decision rules, D-dimer measurements, imaging results, treatments and adverse outcomes up to 30 days MAIN OUTCOME MEASURES: Women were classified as having PE on the basis of imaging, treatment and adverse outcomes by assessors blind to clinical features and D-dimer. Primary analysis was limited to women with conclusive imaging to avoid work-up bias. Secondary analyses included women with clinically diagnosed or ruled out PE. RESULTS: The only clinical features associated with PE on multivariate analysis were age (odds ratio 1.06; 95% confidence interval 1.01-1.11), previous thrombosis (3.07; 1.05-8.99), family history of thrombosis (0.35; 0.14-0.90), temperature (2.22; 1.26-3.91), systolic blood pressure (0.96; 0.93-0.99), oxygen saturation (0.87; 0.78-0.97) and PE-related chest x-ray abnormality (13.4; 1.39-130.2). Clinical decision rules had areas under the receiver-operator characteristic curve ranging from 0.577 to 0.732 and no clinically useful threshold for decision-making. Sensitivities and specificities of D-dimer were 88.4% and 8.8% using a standard threshold and 69.8% and 32.8% using a pregnancy-specific threshold. CONCLUSIONS: Clinical decision rules and D-dimer should not be used to select pregnant or postpartum women with suspected PE for further investigation. Clinical features and chest x-ray appearances may have counter-intuitive associations with PE in this context. TWEETABLE ABSTRACT: Clinical decision rules and D-dimer are not helpful for diagnosing pregnant/postpartum women with suspected PE.

[Angiogenesis-related factors in the placenta of pregnant women with congenital heart diseases]. / Faktory angiogeneza v platsente beremennykh s vrozhdennymi porokami serdtsa.

OBJECTIVE: To study the features of angiogenesis of the placental villous chorion in women whose gestation took place in congenital heart disease (CHD). MATERIAL AND METHODS: Thirty-five placentas obtained from women with full-term pregnancy, including 20 cases of non-operated CHD and 15 as a result of physiological pregnancy and childbirth (a control group), were studied. A placental morphological examination was made according to the standard scheme using routine stains and immunohistochemical techniques involving reactions with mouse monoclonal antibodies against VEGF, CD34, and SMA. RESULTS: The placentas of women with CHD showed a set of pathological changes, including impaired chorionic villous maturation and marked dystrophic and necrobiotic changes, the latter being more common in the placental marginal zones. Placental VEGF expression in women with CHD was significantly higher than that in the controls, especially at the edge of the placental disc. On the contrary, CD34 expression in all placental sections was lower in CHD. The distribution of SMA in the myofibroblasts of chorionic villous vessels in CHD was characterized by diffuse growth of actin expression. The specific volume of the cell surface with a positive reaction to actin significantly increased in the center, especially in the peripheral zone. CONCLUSION: Thus, the analysis of the studies could establish that hemodynamic disturbance during gestation complicated by CHD was accompanied by remodeling of the villous chorion. Pathological changes in the placental barrier complicate metabolism and gas exchange in the fetoplacental complex. Microvascular remodeling is an important mechanism of placental adaptation to circulatory hypoxic conditions in the presence of CHD and a prerequisite for successful pregnancy termination and childbirth in disease.

LGA-newborn from patients with pregestational obesity present reduced adiponectin-mediated vascular relaxation and endothelial dysfunction in fetoplacental arteries.

Maternal obesity is associated with large-for-gestational-age (LGA) neonates and programming of obesity-related cardiovascular disease in the offspring, however, the mechanisms that lead to the later are unclear. Presently, interpretations of NO-dependent changes in vascular function in LGA newborn from obese mothers are conflicting. Adiponectin improves endothelial function by increasing eNOS activity and NO production. We propose that LGAs from obese mothers present a diminished vascular response to adiponectin; thus, affecting eNOS and AMPK activation. Chorionic arteries, umbilical cord and primary cultures of umbilical artery endothelial cells (HUAEC) were collected at term (>38 weeks) from uncomplicated singleton pregnancies of LGA and adequate-for-gestational (AGA) newborn. Vascular reactivity of chorionic plate arteries was assessed by wire myography. mRNA expression of adiponectin receptors 1 (AdipoR1) and AdipoR2 in HUAEC was determined by qPCR. Protein expression of AdipoR1, AdipoR2, AMPK, phospho-AMPKαThr172 , eNOS, and phospho-eNOSSer1177 after stimulation with AdipoRon was determined by Western Blot. Maximal adiponectin-induced chorionic artery relaxation in LGAs was diminished compared to control. In vitro studies showed no differences in expression of AdipoRs, total AMPK and, eNOS activation between groups; however, higher expression of total eNOS and AMPK activation in HUAEC of LGA relative to AGAs were observed. LGA HUAEC showed diminished NO production and eNOS activity compared to AGA in response to AdipoRon but no changes in AMPK activation. Placental endothelium of LGAs shows a diminished vascular response to adiponectin. Moreover, eNOS activation and adiponectin-dependent NO production is lower in HUAEC of LGA from obese mothers, indicating they present dysfuncional placental-endothelial responses.

Venous thromboembolism and women's health.

The prevention and treatment of venous thromboembolism (VTE) poses distinct gender-specific challenges. Women of childbearing age are at an increased risk of VTE secondary to the transient risk factors of combined hormonal contraception (CHC) and pregnancy. Cancers specific to women are associated with a significant burden of VTE; whilst the incidence of VTE in localised breast cancer is 5 per 1000 person-years, more cases are seen due to the prevalence of breast cancer. Treatment of VTE in women can be complicated by abnormal uterine bleeding, now increasingly reported with direct oral anticoagulants (DOACs) as well as vitamin K antagonists. Divergence between international guidelines regarding the use of CHC following an oestrogen-associated VTE and appropriate withdrawal of such contraception requires clarification for clinicians. Additionally, there is uncertainty as to whether to consider such events provoked or unprovoked and, consequently, the optimal duration of treatment in these women remains unclear. During pregnancy and the puerperium, the traditional anticoagulants remain the agents of choice with no further advances in DOAC safety data, and similarly in lactation. Further studies evaluating the safety and optimal treatment strategies in these women are awaited.

Developmental origins of pregnancy-induced cardiac changes: establishment of a novel model using the atrial natriuretic peptide gene-disrupted mice.

Pregnancy evokes many challenges on the maternal cardiovascular system that may unmask predispositions for future disease. This is particularly evident for women who develop pregnancy-related disorders, for example, pre-eclampsia and gestational diabetes or hypertension. Such pregnancy-related syndromes increase the risk for cardiovascular disease (CVD) postpartum. As a result, pregnancy has been termed as a cardiovascular stress test and an indicator or marker to predict the development of CVD later in life. In addition, pregnancy-related disorders impact the development of offspring also placing them at a higher risk for disease. Utilizing pregnancy as a physiological stressor, the current investigation sought to determine whether the cardiovascular system of offspring exposed to gestational hypertension in utero would respond adversely to the stress of pregnancy. Heterozygous atrial natriuretic peptide gene-disrupted (ANP+/-) offspring were generated by either crossing male wildtype ANP+/+ with female knockout ANP-/- to produce ANP+/-KO mice or crossing female wildtype ANP+/+ with male knockout ANP-/- to produce ANP+/-WT mice. To study the cardiovascular stress induced by pregnancy, female ANP+/-WT and ANP+/-KO mice were mated with male wildtype ANP+/+ mice to initiate pregnancy. Cardiac size and molecular expression of the renin-angiotensin (RAS) and natriuretic peptide systems (NPS) were compared between offspring groups. Our data demonstrate that gestational hypertension and lack of maternal ANP did not significantly impact the progression and regression of pregnancy-induced cardiac hypertrophy over gestation and postpartum in ANP+/- offspring. Additionally, the molecular cardiac expression of the RAS and NPS did not differ between offspring groups. Future investigation should assess potential differences in cardiac function and the impact of fetal-programming on offspring cardiovascular adaptations during pregnancy in more severe models of pregnancy-related hypertensive syndrome such as angiotensin II or isoproterenol infusion.

Betaine Aldehyde Dehydrogenase expression during physiological cardiac hypertrophy induced by pregnancy.

Betaine Aldehyde Dehydrogenase (betaine aldehyde: NAD(P)+ oxidoreductase, (E.C. 1.2.1.8; BADH) catalyze the irreversible oxidation of betaine aldehyde (BA) to glycine betaine (GB) and is essential for polyamine catabolism, γ-aminobutyric acid synthesis, and carnitine biosynthesis. GB is an important osmolyte that regulates the homocysteine levels, contributing to a vascular risk factor reduction. In this sense, distinct investigations describe the physiological roles of GB, but there is a lack of information about the GB novo synthesis process and regulation during cardiac hypertrophy induced by pregnancy. In this work, the BADH mRNA expression, protein level, and activity were quantified in the left ventricle before, during, and after pregnancy. The mRNA expression, protein content and enzyme activity along with GB content of BADH increased 2.41, 1.95 and 1.65-fold respectively during late pregnancy compared to not pregnancy, and returned to basal levels at postpartum. Besides, the GB levels increased 1.53-fold during pregnancy and remain at postpartum. Our results demonstrate that physiological cardiac hypertrophy induced BADH mRNA expression and activity along with GB production, suggesting that BADH participates in the adaptation process of physiological cardiac hypertrophy during pregnancy, according to the described GB role in cellular osmoregulation, osmoprotection and reduction of vascular risk.

Peripartum Cardiomyopathy: Do Exosomes Play a Role?

Peripartum cardiomyopathy (PPCM) refers to irreversible cardiomyocyte damage that occurs during the last month of pregnancy, or within 5 months after giving birth. It is characterized by systolic heart failure. This life-threatening condition is relatively uncommon, but the incidence has been climbing up. Because of its high mortality, it is crucial for physicians to have high suspicious for the disease. Studies have been done to search into specific lab test and treatment for PPCM. Therapies like anti-viral, anti-inflammatory and immunosuppression regimen have been explored. New regimen like exosomes has also been explored and revealed promising effects.

Deletion of the Serotonin Receptor Type 3A in Mice Leads to Sudden Cardiac Death During Pregnancy.

BACKGROUND: The serotonin receptor type 3 (Htr3) blocker is associated with QT prolongation and torsades de pointes. However, little is known about effects of Htr3 on the heart arrhythmia. METHODS AND RESULTS: An electrophysiological study Involving knock-out (KO) female mice lacking functional Htr3a (Htr3a(-/-)) and their wild-type littermates during non-pregancy (NP) and late pregnancy (LP) was performed. Htr3a mRNA was present in the wild-type, but not in the Htr3a(-/-)mouse hearts. Serotonin and tryptophan hydroxylase 1 (Tph1), a rate-limiting enzyme of serotonin synthesis in hearts, is increased during pregnancy. The heart weight and size were increased in the pregnant mice regardless of a mutation. The QTc intervals were prolonged after pregnancy in both the wild (NP: 171.2±16.8 vs. LP: 247.7±14.3 ms; P<0.001) and Htr3a(-/-)mice (NP: 187.9±18.7 vs. LP: 275.6±11.0 ms, P<0.001). Compared with wild-type LP mice, Htr3a(-/-)LP mice had increased spontaneous ventricle tarchycardia (VT; 56% vs. 0%, P=0.002), VT inducibility (66% vs. 25%, P=0.002) and mortality (56% vs. 0%, P=0.002). Pharmacologic administration of serotonin and Htr3 agonists (m-CPBG) decreased the QT interval in wild mice, but not in Htr3a(-/-)mice. CONCLUSIONS: Htr3a is present in mouse hearts. Serotonin and Tph1 were increased during pregnancy. The deletion of Htr3a was related to fatal arrhythmias and sudden cardiac death during pregnancy, and its activation reversed the QT prolongation.

Maternal and foetal angiogenic imbalance in congenital heart defects.

AIMS: Animal models showed that angiogenesis is related to abnormal heart development. Our objectives were to ascertain whether a relationship exists between congenital heart defects (CHDs) and angiogenic/anti-angiogenic imbalance in maternal and foetal blood and study the expression of angiogenic factors in the foetal heart. METHODS AND RESULTS: Maternal and cord blood placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) were compared in 65 cases of CHD and 204 normal controls. Angiogenic factor expression and markers of hypoxia were measured in heart tissue from 23 CHD foetuses and 8 controls. In the CHD group, compared with controls, plasma PlGF levels were significantly lower (367 ± 33 vs. 566 ± 26 pg/mL; P < 0.0001) and sFlt-1 significantly higher (2726 ± 450 vs. 1971 ± 130 pg/mL, P = 0.0438). Foetuses with CHD had higher cord plasma sFlt-1 (442 ± 76 vs. 274 ± 26 pg/mL; P = 0.0285) and sEng (6.76 ± 0.42 vs. 4.99 ± 0.49 ng/mL, P = 0.0041) levels. Expression of vascular endothelial growth factor (VEGF), sFlt-1, markers of chronic hypoxia, and antioxidant activity were significantly higher in heart tissue from CHD foetuses compared with normal hearts (VEGF, 1.59-fold; sFlt-1, 1.92-fold; hypoxia inducible factor (HIF)-2α, 1.45-fold; HO-1, 1.62-fold; SOD1, 1.31-fold). CONCLUSION: An intrinsically angiogenic impairment exists in CHD that appears to be present in both the maternal and foetal circulation and foetal heart. Our data suggest that an imbalance of angiogenic-antiangiogenic factors is associated with developmental defects of the human heart.

Molecular mechanisms regulating the vascular prostacyclin pathways and their adaptation during pregnancy and in the newborn.

Prostacyclin (PGI(2)) is a member of the prostanoid group of eicosanoids that regulate homeostasis, hemostasis, smooth muscle function and inflammation. Prostanoids are derived from arachidonic acid by the sequential actions of phospholipase A(2), cyclooxygenase (COX), and specific prostaglandin (PG) synthases. There are two major COX enzymes, COX1 and COX2, that differ in structure, tissue distribution, subcellular localization, and function. COX1 is largely constitutively expressed, whereas COX2 is induced at sites of inflammation and vascular injury. PGI(2) is produced by endothelial cells and influences many cardiovascular processes. PGI(2) acts mainly on the prostacyclin (IP) receptor, but because of receptor homology, PGI(2) analogs such as iloprost may act on other prostanoid receptors with variable affinities. PGI(2)/IP interaction stimulates G protein-coupled increase in cAMP and protein kinase A, resulting in decreased [Ca(2+)](i), and could also cause inhibition of Rho kinase, leading to vascular smooth muscle relaxation. In addition, PGI(2) intracrine signaling may target nuclear peroxisome proliferator-activated receptors and regulate gene transcription. PGI(2) counteracts the vasoconstrictor and platelet aggregation effects of thromboxane A(2) (TXA(2)), and both prostanoids create an important balance in cardiovascular homeostasis. The PGI(2)/TXA(2) balance is particularly critical in the regulation of maternal and fetal vascular function during pregnancy and in the newborn. A decrease in PGI(2)/TXA(2) ratio in the maternal, fetal, and neonatal circulation may contribute to preeclampsia, intrauterine growth restriction, and persistent pulmonary hypertension of the newborn (PPHN), respectively. On the other hand, increased PGI(2) activity may contribute to patent ductus arteriosus (PDA) and intraventricular hemorrhage in premature newborns. These observations have raised interest in the use of COX inhibitors and PGI(2) analogs in the management of pregnancy-associated and neonatal vascular disorders. The use of aspirin to decrease TXA(2) synthesis has shown little benefit in preeclampsia, whereas indomethacin and ibuprofen are used effectively to close PDA in the premature newborn. PGI(2) analogs have been used effectively in primary pulmonary hypertension in adults and have shown promise in PPHN. Careful examination of PGI(2) metabolism and the complex interplay with other prostanoids will help design specific modulators of the PGI(2)-dependent pathways for the management of pregnancy-related and neonatal vascular disorders.

Dysregulation of hydrogen sulfide producing enzyme cystathionine γ-lyase contributes to maternal hypertension and placental abnormalities in preeclampsia.

BACKGROUND: The exact etiology of preeclampsia is unknown, but there is growing evidence of an imbalance in angiogenic growth factors and abnormal placentation. Hydrogen sulfide (H2S), a gaseous messenger produced mainly by cystathionine γ-lyase (CSE), is a proangiogenic vasodilator. We hypothesized that a reduction in CSE activity may alter the angiogenic balance in pregnancy and induce abnormal placentation and maternal hypertension. METHODS AND RESULTS: Plasma levels of H2S were significantly decreased in women with preeclampsia (P<0.01), which was associated with reduced placental CSE expression as determined by real-time polymerase chain reaction and immunohistochemistry. Inhibition of CSE activity by DL-propargylglycine reduced placental growth factorproduction from first-trimester (8-12 weeks gestation) human placental explants and inhibited trophoblast invasion in vitro. Knockdown of CSE in human umbilical vein endothelial cells by small-interfering RNA increased the release of soluble fms-like tyrosine kinase-1 and soluble endoglin, as assessed by enzyme-linked immunosorbent assay, whereas adenoviral-mediated CSE overexpression in human umbilical vein endothelial cells inhibited their release. Administration of DL-propargylglycine to pregnant mice induced hypertension and liver damage, promoted abnormal labyrinth vascularization in the placenta, and decreased fetal growth. Finally, a slow-releasing H2S-generating compound, GYY4137, inhibited circulating soluble fms-like tyrosine kinase-1 and soluble endoglin levels and restored fetal growth in mice that was compromised by DL-propargylglycine treatment, demonstrating that the effect of CSE inhibitor was attributable to inhibition of H2S production. CONCLUSIONS: These results imply that endogenous H2S is required for healthy placental vasculature and that a decrease in CSE/H2S activity may contribute to the pathogenesis of preeclampsia.

C1 esterase inhibitor activity in amniotic fluid embolism.

OBJECTIVES: Amniotic fluid embolism exhibits activation of the complement system and the kallikrein-kinin and coagulofibrinolytic systems. C1 esterase inhibitor is a major inhibitor of C1 esterase and can inhibit plasma kallikrein and also factors XIIa and XIa. Its activity has been shown to be significantly lower in pregnancy and labor than in the nonpregnant state. The purpose of this study was to determine C1 esterase inhibitor activity levels in amniotic fluid embolism. DESIGN: Retrospective study. SETTING: A single university-based center. PATIENTS: One hundred six cases with amniotic fluid embolism in a total of 194 singleton pregnant women between January 2010 and December 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred six cases of amniotic fluid embolism had applied to the Japan amniotic fluid embolism registration center in Hamamatsu University School of Medicine between January 2010 and December 2011. In amniotic fluid embolism cases, 85 cases were nonfatal and 21 cases were fatal. Eighty-eight women who delivered without amniotic fluid embolism were regarded as a control. C1 esterase inhibitor activity levels were significantly lower in amniotic fluid embolism patients (30.0% ± 1.8%) than in control women (62.0% ± 2.0%) (p < 0.0001). C1 esterase inhibitor activity levels in fatal amniotic fluid embolism cases (22.5% ± 3.4%) were significantly lower than those in nonfatal amniotic fluid embolism cases (32.0% ± 2.1%) (p < 0.05). CONCLUSIONS: These results demonstrated that low C1 esterase inhibitor activity levels were closely associated with the pathogenesis of amniotic fluid embolism suggesting that C1 esterase inhibitor activity levels have potential as a prognosis factor of amniotic fluid embolism.

Developmental determinants of cardiac sensitivity to hypoxia.

Cardiac sensitivity to oxygen deprivation changes significantly during ontogenetic development. However, the mechanisms for the higher tolerance of the immature heart, possibilities of protection, and the potential impact of perinatal hypoxia on cardiac tolerance to oxygen deprivation in adults have not yet been satisfactorily clarified. The hypoxic tolerance of an isolated rat heart showed a triphasic pattern: significant decrease from postnatal day 1 to 7, followed by increase to the weaning period, and final decline to adulthood. We have observed significant ontogenetic changes in mitochondrial oxidative phosphorylation and mitochondrial membrane potential, as well as in the role of the mitochondrial permeability transition pores in myocardial injury. These results support the hypothesis that cardiac mitochondria are deeply involved in the regulation of cardiac tolerance to oxygen deprivation during ontogenetic development. Ischemic preconditioning failed to increase tolerance to oxygen deprivation in the highly tolerant hearts of newborn rats. Chronic hypoxic exposure during early development may cause in-utero or neonatal programming of several genes that can change the susceptibility of the adult heart to ischemia-reperfusion injury; this effect is sex dependent. These results would have important clinical implications, since cardiac sensitivity in adult patients may be significantly affected by perinatal hypoxia in a sex-dependent manner.

[The influence of structural and functional disorders in cardiovascular and renal systems and metabolic disturbances on perinatal outcomes in pregnant women with chronic arterial hypertension].

We studied the influence of structural and functional disorders in cardiovascular and renal system and metabolic disturbances on perinatal outcomes in pregnant women with chronic arterial hypertension. The study included 100 women with these pathologies and 30 patients with physiological pregnancy. Comprehensive evaluation of the cardiovascular system, metabolic status, and perinatal outcomes was undertaken. The results indicate that atherogenic dyslipidemia is significantly associated with the reduction of body mass while glomerular filtration rate, concentric and eccentric left ventricular hypertrophy with the decrease of both weight and height of the newborns.

Control of soluble fms-like tyrosine-1 (sFlt-1) production response to placental ischemia/hypoxia: role of tumor necrosis factor-α.

Although abnormal soluble fms-like tyrosine kinase-1 (sFlt-1) production is thought to be an important factor in the pathogenesis of preeclampsia (PE), the mechanisms that regulate the production of sFlt-1 during PE are unclear. While our laboratory has shown tumor necrosis factor-α (TNF-α) and sFlt-1 to be elevated in pregnant rats in response to placental ischemia, the importance of TNF-α in the regulation of sFlt-1 production is unknown. Therefore, the purpose of this study was to determine the role of TNF-α in mediating the increase in sFlt-1 in response to placental ischemia or hypoxia. Reductions in uterine perfusion pressure in pregnant rats significantly increased plasma levels of sFlt-1 and tended to increase TNF-α, an effect markedly attenuated by pretreatment with a TNF-α inhibitor etanercept (0.4 mg/kg). To further assess chronic interactions between TNF-α and sFlt-1, we examined a chronic effect of TNF-α infusion (50 ng/day) into normal pregnant rats to increase plasma sFlt-1 levels, as well as the effects of acute hypoxia on placental sFlt-1 production in the absence and presence of TNF-α blockade. Placental explants exposed to hypoxic conditions had enhanced TNF-α levels versus normoxic conditions, as well as increased sFlt-1 production. Pretreatment of placental explants with etanercept (15 µM) significantly reduced TNF-α levels in response to hypoxia but did not attenuate sFlt-1 production. These data suggest that while TNF-α may not play an important role in stimulating sFlt-1 production in response to acute hypoxia, a more chronic hypoxia, or placental ischemia may be an important stimulus for enhanced sFlt-l production.