Molecular Insights into the Thrombotic and Microvascular Injury in Placental Endothelium of Women with Mild or Severe COVID-19.

Clinical manifestations of coronavirus disease 2019 (COVID-19) in pregnant women are diverse, and little is known of the impact of the disease on placental physiology. Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been detected in the human placenta, and its binding receptor ACE2 is present in a variety of placental cells, including endothelium. Here, we analyze the impact of COVID-19 in placental endothelium, studying by immunofluorescence the expression of von Willebrand factor (vWf), claudin-5, and vascular endothelial (VE) cadherin in the decidua and chorionic villi of placentas from women with mild and severe COVID-19 in comparison to healthy controls. Our results indicate that: (1) vWf expression increases in the endothelium of decidua and chorionic villi of placentas derived from women with COVID-19, being higher in severe cases; (2) Claudin-5 and VE-cadherin expression decrease in the decidua and chorionic villus of placentas from women with severe COVID-19 but not in those with mild disease. Placental histological analysis reveals thrombosis, infarcts, and vascular wall remodeling, confirming the deleterious effect of COVID-19 on placental vessels. Together, these results suggest that placentas from women with COVID-19 have a condition of leaky endothelium and thrombosis, which is sensitive to disease severity.

Morphological changes of red blood cells in peripheral blood smear of patients with pregnancy-related hypertensive disorders.

BACKGROUND AND AIMS: Pregnancy-related hypertensive disorders are complications in which risk factors are identified such as nulliparity, age, malnutrition, obesity and social issues. Those statements are explained by theories of abnormal placentation, immunological inadequacy, genetics and oxidative stress, but all theories converge in endothelial damage, which is able to mechanically deform and hemolyze erythrocytes as they pass through the capillaries. Given the effects of endothelial damage, the aim of the study was to determine erythrocyte alterations in peripheral blood smear of patients with hypertensive disorders of pregnancy that could be used as prognostic condition. METHODS: We performed a prospective, descriptive and observational study where all patients with hypertensive disorders admitted to the obstetrics and gynecology service of a specialty hospital were recruited. Patients who provided signed informed consent underwent peripheral blood smear. Results were tabulated in percentage graphics and analyzed with Cramer's V based on χ(2). The peripheral blood smear consisted of an extended drop of peripheral blood from the patient with subsequent hematological staining done with Romanowsky stain. RESULTS: A total of 119 samples were analyzed; 74% showed abnormal morphology of erythrocytes and the most frequent abnormality was the presence of schistocytes in up to 39% of samples. Descriptive analysis showed a degree of association to independent variables with Cramer's V = 0.41 value (p <0.05). CONCLUSIONS: A high percentage of patients with hypertensive disorders of pregnancy show some morphologic alterations of erythrocytes in peripheral blood smear.

Anatomical and physiological changes in the venous system of lower limbs in pregnant women and findings associated with the symptomatology.

PURPOSE: Quantify the volume and diameter of veins in the lower limbs of primigravidae and associate the presence of venous signs and symptoms with the vascular measurements. METHODS: A cross-sectional study assessed 64 lower limbs of 32 healthy women of whom 16 were primigravidae between 22 and 36 weeks pregnant, and 16 nulligravidae. The women were submitted to physical assessment, air plethysmography and vascular ultrasound. The volumes and diameters of the main veins in the lower limbs were compared between pregnant and non-pregnant women. In the group of pregnant women, the attempt was also made to associate such measurements to the presence of vascular signs and symptoms. RESULTS: The average venous volume of the lower limbs (110.1 ± 30.2 and 94.7 ± 27.3 mL; p = 0.036), as well as the diameters of the common femoral (12.72 ± 2.27 and 10.14 ± 1.24 mm; p < 0.0001), saphenous (4.81 ± 1.15 and 3.55 ± 0.98 mm; p < 0.0001) and popliteal (6.87 ± 1.68 and 5.36 ± 1.07 mm; p < 0.0001) veins were, respectively, greater in the pregnant women compared with the control group. In pregnant women with venous stasis symptoms, a venous diameter of the saphenous vein compared to those without no symptoms (5.05 ± 1.19 and 4.09 ± 0.70 mm; p = 0.011) was noted. CONCLUSIONS: Anatomical and functional changes in the venous system during pregnancy were detected by the air plethysmography and the vascular ultrasound in primigravidae. In pregnant women, the presence of venous stasis symptoms found an anatomical and functional substrate detected in the differences in diameter of the saphenous vein.

Rest left ventricular function and contractile reserve by dobutamine stress echocardiography in peripartum cardiomyopathy.

AIMS: To assess whether contractile reserve during dobutamine stress echocardiography (DSE) can predict left ventricular functional recovery in patients with peripartum cardiomyopathy and to assess myocardial fibrosis by magnetic resonance imaging (MRI) in these patients. METHODS: Nine patients with peripartum cardiomyopathy were enrolled. All patients underwent DSE and were followed for six months, when a rest Doppler echocardiogram was repeated. MRI was also performed at the beginning of follow-up to identify myocardial fibrosis. RESULTS: Mean age was 29±7.9 years and mean left ventricular ejection fraction at baseline was 39.4±8.6% (range 24-49%). Eight of the nine patients showed left ventricular functional recovery with mean ejection fraction at follow-up of 57.1±13.8%. The ejection fraction response to DSE did not predict recovery at follow-up. On the other hand, left ventricular ejection fraction at baseline correlated with ejection fraction at follow-up. Mild fibrosis was detected in only one patient. CONCLUSION: Left ventricular ejection fraction at baseline was a predictor of left ventricular functional recovery in patients with peripartum cardiomyopathy. Dobutamine stress echocardiography at presentation of the disease did not predict recovery at follow-up. Myocardial fibrosis appeared to be uncommon in this cardiomyopathy.

[Microangiopathy in preeclampsia: the usefulness of the peripheral blood smear]. / Microangiopatía en la preeclampsia: utilidad del frotis de sangre periférica.

Endothelial dysfunction is a fundamental characteristic in the physiopathology of preeclampsia. Currently, a series of markers which explain endothelial dysfunction have been identified. The recognition of endothelial dysfunction has been used to realize an early diagnosis of preeclampsia, as soon as the classification of a possible prognosis. Nevertheless the detection of these markers is not accessible to the majority of hospitable centers that treat patients with preeclampsia. One indirect marker of endothelial dysfunction with a greater accessibility is the assessment of peripheral blood smear. Several studies had proved the presence of endothelial dysfunction by identification of red blood cells crenated in peripheral blood smear led us also to measure the impact in the evolution of the disease.

Bothrops jararaca peptide with anti-hypertensive action normalizes endothelium dysfunction involved in physiopathology of preeclampsia.

Preeclampsia, a pregnancy-specific syndrome characterized by hypertension, proteinuria and edema, is a major cause of fetal and maternal morbidity and mortality especially in developing countries. Bj-PRO-10c, a proline-rich peptide isolated from Bothrops jararaca venom, has been attributed with potent anti-hypertensive effects. Recently, we have shown that Bj-PRO-10c-induced anti-hypertensive actions involved NO production in spontaneous hypertensive rats. Using in vitro studies we now show that Bj-PRO-10c was able to increase NO production in human umbilical vein endothelial cells from hypertensive pregnant women (HUVEC-PE) to levels observed in HUVEC of normotensive women. Moreover, in the presence of the peptide, eNOS expression as well as argininosuccinate synthase activity, the key rate-limiting enzyme of the citrulline-NO cycle, were enhanced. In addition, excessive superoxide production due to NO deficiency, one of the major deleterious effects of the disease, was inhibited by Bj-PRO-10c. Bj-PRO-10c induced intracellular calcium fluxes in both, HUVEC-PE and HUVEC, which, however, led to activation of eNOS expression only in HUVEC-PE. Since Bj-PRO-10c promoted biological effects in HUVEC from patients suffering from the disorder and not in normotensive pregnant women, we hypothesize that Bj-PRO-10c induces its anti-hypertensive effect in mothers with preeclampsia. Such properties may initiate the development of novel therapeutics for treating preeclampsia.

Alteraciones clínico-metabólicas en mujeres con diabetes gestacional previa / Clinical metabolic disorders in women with previous gestational diabetes

Conocer la frecuencia de diabetes y otros factores de riesgo cardiovascular en mujeres con diabetes mellitus gestacional (DMG) previa. Se evaluaron 92 mujeres con DMG previa, a quienes no se les había diagnosticado diabetes, que asistieron a la pesquisa posparto inicial o anual durante 2008. Se determinó presión arterial, circunferencia abdominal (CA) e índice de masa corporal (IMC). Se practicó prueba de tolerancia oral a la glucosa, medición de niveles de insulina y lípidos séricos. Se estableció la presencia de síndrome metabólico (SM), aplicando los criterios ATP III e índice de resistencia a la insulina mediante el modelo Homa-R. Se usó t Student para la asociación de variables. La media de edad fue 34,7 ± 6,6 años y del período posparto, 3,5 ± 2,6 años. En 8,7 por ciento se hizo el diagnóstico de diabetes, 32,6 por ciento intolerancia a la glucosa y 12,0 por ciento, glucemia alterada en ayunas. 62,1 por ciento presentaba obesidad abdominal, 62,5 por ciento, algún tipo de dislipidemia y 23,80 por ciento, elevación de la presión arterial. 46,4 por ciento reunía los criterios de SM y 29,6 por ciento mostró un índice HOMA-R > 2,5. Las cifras de CA, IMC, triglicéridos, glucemia basal, glucemia 2 horas post-carga, e insulina 2 horas poscarga fueron más altas (P< 0,05) en mujeres con anormalidades de la tolerancia a la glucosa que en aquellas con tolerancia normal. Las mujeres con DMG previa muestran una elevada frecuencia de alteraciones clínicas y metabólicas que representan un potencial incremento del riesgo cardiovascular en un grupo poblacional relativamente joven

To know the frequency of diabetes and other cardiovascular risk factors in women with previous gestational diabetes mellitus (GDM). 92 women with previous GDM, without diagnosis of diabetes, who underwent initial or annual postpartum diabetes screening during 2008, were assessed. Blood pressure, abdominal circumference and body mass index were measured. They were tested for an oral glucose tolerance test (OGTT) and determination of plasma insulin and lipid levels. Metabolic syndrome (MS) was diagnosed according ATP III criteria and the HOMA-R model was used for the insulin resistance index calculation. Student’s t test was used for variables association. The average age was 34.7 ± 6.6 years and postpartum period, 3.5 ± 2.6 years. 8.7 percent was diagnosed with diabetes, 32.6 percent with impaired glucose tolerance and 12.0 percent with impaired fasting glucose. 62.1 percent showed abdominal obesity, 62.5 percent presented some type of dyslipidemia and 23.8 percent, high blood pressure. 46.4 percent met the criteria for MS, and 29.6 percent showed a HOMA-R Index > 2.5. Abdominal circumference, body mass index, blood pressure, triglycerides, basal glucose, 2-h post-load glucose and 2-h post-load insulin values were higher (P< 0.05) in women with abnormal glucose tolerance than those with normal glucose tolerance. Women with previous GDM show a high frequency of clinical and metabolic abnormalities that point towards a potential increase of cardiovascular risk in a relatively young population

Passive mechanical properties of cardiac tissues in heart hypertrophy during pregnancy.

We evaluated changes in passive mechanical properties in cardiac tissues during rat pregnancy. Left and right ventricular free walls were dissected from hearts of nonpregnant, late-pregnant, and postpartum rats. Mechanical experiments in ventricular strips were done by stretch-release cycles using a step motor. The results show that during pregnancy, there is cardiac hypertrophy associated with (1) an increase in myocyte size, particularly of augmented myocyte length, (2) a decrease in passive tension developed by the myocardial walls, and (3) a decrease in both elastic modulus and hysteresis. All changes observed during rat pregnancy were reversed during postpartum. In conclusion, a heart with less ventricular rigidity could contribute to facilitating the ventricular filling in conditions of a greater circulating volume characteristic of pregnancy.

[Histopathological changes in human placentas related to hypertensive disorders]. / Alterações histopatológicas em placentas humanas relacionadas às síndromes hipertensivas.

PURPOSE: to determine the prevalence of histopathological changes, in human placentas, related to hypertensive syndromes. METHODS: a transversal study that compares histopathological changes identified in 43 placentae from hypertensive pregnant women (HypPr), with the ones from 33 placentae from normotensive pregnant women (NorPr). The weight, volume and macroscopic and microscopic occurrence of infarctions, clots, hematomas, atherosis (partial obliteration, thickness of layers and presence of blood vessels hyalinization) and Tenney-Parker changes (absent, discreet and prominent), as well as the locating of infarctions and clots (central, peripheral or the association of both) have been analyzed. The chi2 and t Student tests have been used for the statistical analysis, as well as medians, standard deviations and ratios. It has been considered as significant, p<0.05. RESULTS: the macroscopic study of HypPr placentae have presented lower weight (461.1 versus 572.1 g) and volume (437.4 versus 542.0 cm(3)), higher infarction (51.2 versus 45.5%; p<0.05: OR=1.15) and clots (51.2 versus 15.1%; p<0.05; OR=5.4) ratios, as compared to the NorPr's. In the HypPr and NorPr, microscopic clots have occurred in 83.7 versus 45.5% (p<0.05; OR=4.3), respectively. Atherosis and Tenney-Parker changes have been statistically associated to the hypertensive syndromes (p<0.05). CONCLUSIONS: the obtained data allow us to associate lower placentary weight and volume, higher ratio of macro and microscopic infarction, clots, atherosis and Tenney-Parker changes to placentae of gestations occurring with hypertensive syndromes.

Alterações histopatológicas em placentas humanas relacionadas às síndromes hipertensivas / Histopathological changes in human placentas related to hypertensive disorders

OBJETIVO: determinar a prevalência de alterações histopatológicas em placentas humanas, relacionadas às síndromes hipertensivas. MÉTODOS: estudo de corte transversal, que comparou as alterações histopatológicas identificadas em 43 placentas oriundas de gestantes do grupo de hipertensas (GrHip) com as de 33 placentas de gestantes do grupo de normotensas (GrNor). Foram analisados o peso, volume e ocorrência macro e microscópica de infartos, coágulos, hematomas, aterose (obliteração parcial, espessamento de camadas e presença de vasos hialinizados) e alterações de Tenney-Parker (ausentes, discretas e proeminentes), bem como a localização de infartos e coágulos (central, periférico ou associação de ambos). Para a análise estatística foram usados os testes do χ2 e t de Student, bem como médias, desvios padrões e percentuais. Considerou-se como significante um p<0,05. RESULTADOS: o estudo macroscópico revelou que as placentas do GrHip, se comparadas às do GrNor, apresentaram menor peso (461,1 versus 572,1 g) e volume (437,4 versus 542,0 cm³) e percentuais aumentados de infartos (51,2 versus 45,5 por cento; p<0,05; OR=1,15) e de coágulos (51,2 versus 15,1 por cento; p<0,05; OR=5,4). Nos GrHip e GrNor, os infartos microscópicos ocorreram em 83,7 e 45,5 por cento; p<0,05; OR=4,3, respectivamente. A aterose e as alterações de Tenney-Parker associaram-se estatisticamente às síndromes hipertensivas (p<0,05). CONCLUSÕES: os dados obtidos permitem associar menor peso e volume placentário, maior percentual de infartos macro e microscópicos, coágulos, aterose e alterações de Tenney-Parker às placentas relacionadas com gestações que cursaram com síndromes hipertensivas.

PURPOSE: to determine the prevalence of histopathological changes, in human placentas, related to hypertensive syndromes. METHODS: a transversal study that compares histopathological changes identified in 43 placentae from hypertensive pregnant women (HypPr), with the ones from 33 placentae from normotensive pregnant women (NorPr). The weight, volume and macroscopic and microscopic occurrence of infarctions, clots, hematomas, atherosis (partial obliteration, thickness of layers and presence of blood vessels hyalinization) and Tenney-Parker changes (absent, discreet and prominent), as well as the locating of infarctions and clots (central, peripheral or the association of both) have been analyzed. The χ2 and t Student tests have been used for the statistical analysis, as well as medians, standard deviations and ratios. It has been considered as significant, p<0.05. RESULTS: the macroscopic study of HypPr placentae have presented lower weight (461.1 versus 572.1 g) and volume (437.4 versus 542.0 cm³), higher infarction (51.2 versus 45.5 percent; p<0.05: OR=1.15) and clots (51.2 versus 15.1 percent; p<0.05; OR=5.4) ratios, as compared to the NorPr's. In the HypPr and NorPr, microscopic clots have occurred in 83.7 versus 45.5 percent (p<0.05; OR=4.3), respectively. Atherosis and Tenney-Parker changes have been statistically associated to the hypertensive syndromes (p<0.05). CONCLUSIONS: the obtained data allow us to associate lower placentary weight and volume, higher ratio of macro and microscopic infarction, clots, atherosis and Tenney-Parker changes to placentae of gestations occurring with hypertensive syndromes.

Estudo da morfologia vascular do leito placentário na hipertensão arterial crônica / Morphology of the vascular placental bed in chronic arterial hypertension

OBJETIVO: Analisar os padrões histopatológicos das artérias do leito placentário em gestações complicadas por hipertensão arterial crônica (HAC) comparando-os com o de grávidas normais. MÉTODOS: Biópsias de leito placentário, segundo técnica de Robertson et al.1, foram realizadas em pacientes com idade gestacional igual ou superior a 28 semanas, submetidas a cesárea, após a dequitação. O grupo controle (GC) foi composto por 25 pacientes normais e o grupo de estudo composto por 13 pacientes com HAC leve (HL), 11 pacientes com HAC moderada (HM) e 11 pacientes com HAC grave (HG). As classes de hipertensão foram consideradas leve (PAD 90 - 100 mmHg), moderada (PAD 100 - 110 mmHg) e grave (PAD3 > 110mmHg). Os padrões histológicos das artérias espiraladas foram classificados em: padrão inalterado, modificações fisiológicas, desorganização da camada média, alterações hiperplásicas, necrose e aterose aguda. RESULTADOS: 1) Os achados anormais foram predominantes no grupo de hipertensas, sendo mais freqüente nos grupos HM e HG. 2) O achado anormal mais prevalente foi a desorganização da camada média, com distribuição semelhante nos grupos HM e HG. 3) Os padrões normais ocorreram nos grupos GC e HL, com distribuição semelhante entre si.

OBJECTIVES: To analyze histopathological patterns of placental bed arteries in pregnancies complicated by chronic arterial hypertension. Alterations were considered according to clinical classification of the hypertensive disorders as mild (MG); moderate (MoG) and severe (SG) for comparison with uncomplicated pregnancies, control group (CG). METHODS: Placental bed biopsy was performed in 60 pregnant women; the study group was comprised of pregnant women with hypertension, subdivided in 13 with severe chronic hypertension (CH), 11 with moderate CH and 11 with mild CH, and results were compared to 25 placental bed biopsies from uncomplicated pregnancies. All the pregnant women had a gestational age of at least 28 weeks of gestation with a live fetus and were submitted to cesarean section. Hypertension was considered mild with diastolic blood pressure (DBP) 90 I? 100 mmHg, moderate DBP 100 I? 110 mmHg and severe DBP = 110 mmHg. Placental bed variables selected for histological analysis were: unaltered patterns, physiological changes, medial layer disorganization, medial and intimal hyperplasic changes, acute necrosis and atherosis. RESULTS: In cases with SG and MoG there was predominance of abnormal histophysiological findings: medial layer disorganization and hyperplasic changes, with a statistically significant difference when compared to MG and CG. Alteration in the medial layer was observed in these cases. The normal pattern, unaltered patterns and physiologic changes were more frequent in CG and MG. Physiological changes were the most usual finding, further, there was no acute necrosis or atherosis. CONCLUSION: 1. Abnormal histophysiological findings were predominant in hypertensive pregnant women compared to the normotensive ones; 2. These patterns were more frequent, according to the severity of the hypertensive disorders: Severe, Moderate and Mild; 3. More significant abnormal findings were a change in the medial layer, mainly in...

Atenolol reduces salivary activity in pups of spontaneously hypertensive and normotensive rats treated during pregnancy and lactation.

The salivary activity in pups of spontaneously hypertensive rats (SHR) and Wistar (W) rats treated with atenolol during pregnancy, and lactation was evaluated. Atenolol's anti-hypertensive effect on the SHR rats was noticed from the beginning of treatment. Atenolol-treated SHR and Wistar rat pups showed a decrease in salivary gland weight, salivary flow, and protein concentration, with no alteration in salivary amylase activity. Atenolol's effect on salivary glands can interfere with oral health maintenance.