Henri Augusto Korkes

Lipidomic Assessment of Plasma and Placenta of Women with Early-Onset Preeclampsia

Introduction Adipose tissue is responsible for triggering chronic systemic inflammatory response and these changes may be involved in the pathophysiology of preeclampsia. Objective To characterize the lipid profile in the placenta and plasma of patients with preeclampsia. Methodology Samples were collected from placenta and plasma of 10 pregnant women with preeclampsia and 10 controls. Lipids were extracted using the Bligh–Dyer protocol and were analysed by MALDI TOF-TOF mass spectrometry. Results Approximately 200 lipid signals were quantified. The most prevalent lipid present in plasma of patients with preeclampsia was the main class Glycerophosphoserines-GP03 (PS) representing 52.30% of the total lipid composition, followed by the main classes Glycerophosphoethanolamines-GP02 (PEt), Glycerophosphocholines-GP01 (PC) and Flavanoids-PK12 (FLV), with 24.03%, 9.47% and 8.39% respectively. When compared to the control group, plasma samples of patients with preeclampsia showed an increase of PS (p<0.0001), PC (p<0.0001) and FLV (p<0.0001). Placental analysis of patients with preeclampsia, revealed the PS as the most prevalent lipid representing 56.28%, followed by the main class Macrolides/polyketides-PK04 with 32.77%, both with increased levels when compared with patients control group, PS (p<0.0001) and PK04 (p<0.0001). Conclusion Lipids found in placenta and plasma from patients with preeclampsia differ from those of pregnant women in the control group. Further studies are needed to clarify if these changes are specific and a cause or consequence of preeclampsia.

Relationship between hypoxia and downstream pathogenic pathways in preeclampsia

ABSTRACT Defects in angiogenesis and mitochondrial function in the placenta contribute to the pathogenesis of preeclampsia; however upstream regulators of these pathways are not known. It has been argued that placental hypoxia secondary to abnormal spiral artery remodeling may play a causal role in the angiogenic and mitochondrial abnormalities noted in preeclampsia. The aim of this study was to evaluate the relationship between hypoxia-inducible factor-1α (HIF-1α) ¸ a surrogate of hypoxia, and soluble fms-tyrosine kinase 1 (sFlt1), a circulating anti-angiogenic factor, and microRNA 210 (miR-210), a microRNA that regulates mitochondrial function, in human placentas from preeclamptic and non-hypertensive pregnancies. We first confirmed a 2.5-fold upregulation of HIF-1α protein in placentas from preeclampsia when compared to non-hypertensive controls. Consistent with prior studies, we also observed a 10-fold upregulated sFlt1 mRNA and 2-fold upregulated miR-210 in preeclamptic tissue. Interestingly, while sFlt1 mRNA correlated with miR-210 in preeclampsia (R2 = 0.77, p = 0.0004), there were no significant correlations between these molecules and HIF1α expression. We conclude that non-hypoxia pathways may be involved in the abnormal angiogenic and metabolic alterations noted in preeclampsia.

sFlt-1/PlGF ratio as a prognostic marker of adverse outcomes in women with early-onset preeclampsia

Soluble fms-like tyrosine kinase 1 (sFlt-1) is an anti-angiogenic factor released in higher amounts by preeclamptic placentas and it has been implicated in the endothelial dysfunction observed in the disease. In this study we evaluated if circulating sFlt-1/PlGF ratio is useful to predict adverse outcomes in women with early-onset preeclampsia. This is a cohort study of 88 preeclamptic women with singleton pregnancies at ⩽35weeks of gestation. According to definitions used, adverse outcomes occurred in 46.5% (N=43) of the patients. The median sFlt1/PlGF ratio (25th-75th centile) for all patients evaluated was of 42.26 (13.1-226.1). The median sFlt-1/PlGF ratio among women who had any adverse outcome (N=43) versus no adverse outcomes (N=45) was of 227.6 (80.3-346.1) versus 14.4 (3.35-30.0), (P<0.0001). According to our analyses a sFlt-1/PlGF ratio cut-point of ⩾85 gave a sensitivity of 74.0% and specificity of 97.0%. The positive predictive value and the negative predictive value were 96.0% and 80.0%, respectively. The median sFlt-1/PlGF ratio (25th-75th centile) for patients who delivered within <7days was 260.0 (127.7-404.7) as compared to 14.4 (3.35-34.97) for those patients who delivered within two weeks or more (P<0.0001). Our results suggest that sFlt-1/PlGF ratio is a promising marker for adverse outcomes in women with early-onset preeclampsia.

Similaridade entre os valores da pressão arterial aferida pelo método auscultatório com aparelho de coluna de mercúrio e o método oscilométrico automático com aparelho digital

INTRODUCTION: One of the biggest challenges in the management of hypertension is adequate blood pressure (BP) control. To achieve this goal, home blood pressure measurement (HBPM) with automated devices has been encouraged. However, part of the medical community still disputes its validity, believing that HBPM may lead to incorrect readings. OBJECTIVE: To evaluate the correspondence between the simultaneous measurements of BP with the auscultatory method and an oscillometric digital method, commonly used in HBPM. METHODS: BP was determined simultaneously in 423 individuals (normotensive and hypertensive) with a validated automated digital device (ONROM 705IT) and with the auscultatory method with a mercury sphygmomanometer. Both devices were connected through a Y-shaped connection to a cuff whose size was adjusted to the arm circumference. RESULTS: The values represent mean ± SD (minimum-maximum values): age 40.8 ± 16.3 years (18-92), arm circumference 28.2 ± 3.7 cm (19-42), systolic BP (SBP) auscultatory 127.6 ± 22.8 mmHg (69-223), SBP automated 129.5 ± 23.0 mmHg (56-226), diastolic BP (DBP) auscultatory 79.5 ± 12.6 mmHg (49-135) DBP automated 79.0 ± 12.6 mmHg (48-123). The mean difference in SBP between the two methods was 1.9 mmHg (-15 to +19) and 0.5 mmHg for DBP (-19 to +13). The Bland-Altman analysis showed clinically acceptable agreement between the methods. CONCLUSION: BP measured with the automated method closely mirrors that determined with the conventional auscultatory method and should be used to improve the diagnosis and control of hypertension.

Myomectomy in the second trimester of pregnancy: case report

Uterine leiomyomas are characterized as a benign disease and are observed in 2 to 3% of all normal pregnancies. Out of these, about 10% may present complications during pregnancy. We present a case of a pregnant patient sought emergency obstetric care at the 17th week, complaining of severe pain, presenting with painful abdominal palpation and sudden positive decompression. Ultrasonography revealed a myoma nodule measuring 9.1 x 7.7 cm; the patient was hospitalized and medicated, being also submitted to laparotomy and myomectomy due to worsening of her condition. Prenatal care revealed no further abnormalities, with resolution of gestation at 39 weeks. The newborn weighed 3,315 g, with Apgar scores of 9 and 10. In such cases, clinical treatment should always be attempted and surgery should be considered only in selected cases, mainly in the impossibility of conservative treatment or when the patients clinical features require immediate intervention. In this case, myomectomy was effective against maternal-fetal obstetric complications.

Induced Human Decidual NK-Like Cells Improve Utero-Placental Perfusion in Mice

Decidual NK (dNK) cells, a distinct type of NK cell, are thought to regulate uterine spiral artery remodeling, a process that allows for increased blood delivery to the fetal-placental unit. Impairment of uterine spiral artery remodeling is associated with decreased placental perfusion, increased uterine artery resistance, and obstetric complications such as preeclampsia and intrauterine growth restriction. Ex vivo manipulation of human peripheral blood NK (pNK) cells by a combination of hypoxia, TGFß-1 and 5-aza-2’-deoxycytidine yields cells with phenotypic and in vitro functional similarities to dNK cells, called idNK cells. Here, gene expression profiling shows that CD56Bright idNK cells derived ex vivo from human pNK cells, and to a lesser extent CD56Dim idNK cells, are enriched in the gene expression signature that distinguishes dNK cells from pNK cells. When injected into immunocompromised pregnant mice with elevated uterine artery resistance, idNK cells homed to the uterus and reduced the uterine artery resistance index, suggesting improved placental perfusion.

Human fetal malformations associated with the use of an angiotensin II receptor antagonist: Case Report

INTRODUCTION The potential risks related to drug exposure during pregnancy represent a vast chapter in modern obstetrics and data regarding the safety of antihypertensive drugs during pregnancy are relatively scarce. CASE REPORT A 37-year-old patient discovered her fifth pregnancy at our hospital after 26 weeks and 4 days of gestation. She reported a history of hypertension and was currently being treated with Losartan. Hospitalization was recommended for the patient and further evaluation of fetal vitality was performed. On the fourth day an ultrasound was performed, resulting in a severe oligohydramnios, fetal centralization and abnormal ductus venosus. After 36 hours, the newborn died. Pathologic evaluation: At autopsy, the skullcap had large fontanels and deficient ossification. The kidneys were slightly enlarged. A microscopic examination detected underdevelopment of the tubules and the presence of some dilated lumens. Immunohistochemical detection of epithelial membrane antigen was positive. Immunoreactivity of CD 15 was also assayed to characterize the proximal tubules, and lumen collapse was observed in some regions. DISCUSSION Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor antagonists (ARAs) are among the most widely prescribed drugs for hypertension. They are often used by hypertensive women who are considering become pregnant. While their fetal toxicity in the second or third trimesters has been documented, their teratogenic effect during the first trimester has only recently been demonstrated. CONCLUSION Constant awareness by physicians and patients should be encouraged, particularly in regard to the prescription of antihypertensive drugs in women of childbearing age who are or intend to become pregnant.

[31-OR]: Modeling an NK cell based immunotherapy for preeclampsia

Objectives Natural Killer (NK) cells are key regulators of normal placental development. In contrast to peripheral blood NK (pNK) cells, NK cells located at the maternal-fetal interface constitute the main local lymphocyte population in early pregnancy, are non-cytotoxic and pro-angiogenic. Decidual NK cells (dNK) regulate remodeling of uterine spiral arteries (SA), a process leading to increased blood supply to the developing fetal–placental unit. When SA remodeling is impaired, reduced placental perfusion results in elevated plasma sFlt1 levels, triggering preeclampsia systemic symptoms, (hypertension, edema and proteinuria). We aim to model a NK cell based therapy for preeclampsia. Methods Ex vivo manipulation of human pNK cells by a combination of hypoxia, TGFb-1 and 5-aza-2′-deoxycytidine (AZA) yields cells, termed idNK cells, with phenotypic and in vitro functional similarities to dNK cells including expression of dNK cell surface markers and chemokine receptors, proangiogenic capacity and reduced cytotoxicity. idNK cells were further characterized by microarray gene expression profiling, and their capacity to remodel SA was evaluated in immunodeficient mice presenting narrow SA. Results Although distinct from dNK cells, idNK cells acquired the gene expression signature that differentiates dNK cells from pNK cells. Most importantly, i-dNK cell injection increased placental perfusion in a mouse model with narrow SA as evidenced by decreased uterine artery resistance evaluated by Doppler ultrasound, and ameliorated SA remodeling. Conclusions Ex vivo conversion of peripheral blood NK cells into i-dNK cells may be a potential approach for the prevention or treatment of preeclampsia and related disorders. Disclosures R. de Carvalho Cavalli: None. A. Cerdeira: None. H. Korkes: None. S. Burke: None. A. Rajakumar: None. M. Bhasin: None. S. Karumanchi: Consultant, Commercial Interest: Aggamin LLC. H. Kopcow: None.

PP138. Human fetal malformations associated with the use of angiotensin II receptor antagonist

INTRODUCTION antagonists of angiotensin II receptor (AAR) are commonly used for the treatment of chronic hypertension in the general population. Some of these pharmacological agents are losartan, candesartan, valsartan and tasosartan. Despite the good response achieved with these drugs in the control of hypertension, all medications that act directly on the renin-angiotensin system should be contraindicated during pregnancy. These drugs have been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death.Here we report a case of fetal malformations and death associated with the use of losartan. OBJECTIVES describing the association of fetal malformations and the use of losartan during first and second trimester of pregnancy. METHODS this is a case report involving a 37-year-old pregnant woman at 26 gestational weeks. This patient had history of chronic hypertension for more than five years that was being regularly treated with Losartan 50mg/day. After her first consultation losartan was promptly discontinued and substituted for methyldopa. However, scan evaluation demonstrated severe oligohydramnios associated with altered fetal biophysical profile and altered Doppler fluxometry (absent diastolic flow at umbilical arteries). Therefore, a cesarean-section was performed after corticoid administration for fetal lung maturation. At first moment some characteristic alterations as fetal limb contractures and craniofacial deformation were detected at the 1007g new-born. This baby went to death 36h after delivery due to severe lung hypoplasia. RESULTS the autopsy examination revealed renal tubular dysgenesis associated with changes secondary to nephropathy, probably induced by drug (Fig. 1). Associated findings were underdevelopment of bones of the skull with large fontanelles, thymus atrophy and signs of perinatal hypoxia. CONCLUSION the difficulty of attending basic health assistance was attributed to be associated with this case, as this patient did not have opportunity and sufficient information about the necessity of changing her medication during pregnancy. Apart from this situation, this case report brings good information about the association between antagonists of angiotensin II receptor and human fetal malformations.