Stretch-induced compliance mechanism in pregnancy-induced cardiac hypertrophy and the impact of cardiovascular risk factors.

Pressure overload-induced hypertrophy compromises cardiac stretch-induced compliance (SIC) after acute volume overload (AVO). We hypothesized that SIC could be enhanced by physiological hypertrophy induced by pregnancy's chronic volume overload. This study evaluated SIC-cardiac adaptation in pregnant women with or without cardiovascular risk (CVR) factors. Thirty-seven women (1st trimester, 1stT) and a separate group of 31 (3rd trimester, 3rdT) women [healthy or with CVR factors (obesity and/or hypertension and/or with gestational diabetes)] underwent echocardiography determination of left ventricular end-diastolic volume (LVEDV) and E/e' before (T0), immediately after (T1), and 15 min after (T2; SIC) AVO induced by passive leg elevation. Blood samples for NT-proBNP quantification were collected before and after the AVO. Acute leg elevation significantly increased inferior vena cava diameter and stroke volume from T0 to T1 in both 1stT and 3rdT, confirming AVO. LVEDV and E/e' also increased immediately after AVO (T1) in both 1stT and 3rdT. SIC adaptation (T2, 15 min after AVO) significantly decreased E/e' in both trimesters, with additional expansion of LVEDV only in the 1stT. NT-pro-BNP increased slightly after AVO but only in the 1stT. CVR factors, but not parity or age, significantly impacted SIC cardiac adaptation. A distinct functional response to SIC was observed between 1stT and 3rdT, which was influenced by CVR factors. The LV of 3rdT pregnant women was hypertrophied, showing a structural limitation to dilate with AVO, whereas the lower LV filling pressure values suggest increased diastolic compliance.NEW & NOTEWORTHY The sudden increase of volume overload triggers an acute myocardial stretch characterized by an immediate rise in contractility by the Frank-Starling mechanism, followed by a progressive increase known as the slow force response. The present study is the first to characterize echocardiographically the stretch-induced compliance (SIC) mechanism in the context of physiological hypertrophy induced by pregnancy. A distinct functional adaptation to SIC was observed between first and third trimesters, which was influenced by cardiovascular risk factors.

Increasing systemic chronic inflammation mediated the association between poor sleep during pregnancy and gestational cardiovascular health.

OBJECTIVES: This study aimed to examine the association between sleep behaviors and cardiovascular health (CVH) during pregnancy and test whether high-sensitivity C-reactive protein (hs-CRP) mediates this association. METHODS: The study included 4204 pregnant women from the Maternal and Infant Health cohort study in Hefei (MIH-Hefei). Information on sleep (chronotype, sleep duration, snoring, daytime sleepiness, and insomnia) was collected through a touch-screen structured questionnaire at 16-23 weeks' gestation. CVH (body mass index, blood pressure, total cholesterol, glucose, and smoking) and hs-CRP were measured at 24-28 weeks' gestation. The role of hs-CRP in the association between sleep and CVH was explored in a mediation analysis, while adjusting for multiple confounding factors. RESULTS: Poor sleep score was significantly associated with poor gestational CVH metrics, including an RR of 0.872 (95% CI, 0.810, 0.938) for having all ideal (vs. any nonideal) CVH metrics; hs-CRP level was significantly associated with poor gestational CVH metrics, including an RR of 0.531 (95% CI, 0.432, 0.609) for having all ideal (vs. any nonideal) CVH metrics. Sleep scores were positively correlated with hs-CRP level (ß, 0.020, 95% CI, 0.006, 0.034). Mediation analysis revealed that the association between sleep and CVH mediated by hs-CRP was 12.31% (indirect effect, -0.0095, 95% CI, -0.0167, -0.0042). CONCLUSIONS: Poor sleep during pregnancy, particularly late chronotype and snoring, may worsen CVH by increasing systemic chronic inflammation.

Study of serum miR-518 and its correlation with inflammatory factors in patients with gestational diabetes mellitus complicated with hypertensive disorder complicating pregnancy.

OBJECTIVE: Gestational diabetes mellitus (GDM) and hypertensive disorder complicating pregnancy (HDCP) are common complications during pregnancy. This study estimated the correlation of serum miR-518 and inflammatory factors in GDM complicated with HDCP patients (GDM&HDCP). METHODS: Total 240 pregnant women were enrolled, including 118 cases with GDM alone, 57 cases with GDM&HDCP, and 65 healthy pregnant women. The expressions of serum miR-518 and PPARα were detected by RT-qPCR. The clinical diagnostic efficacy of miR-518 for GDM and GDM&HDCP was analyzed via ROC curve. Pearson coefficient was used to analyze the correlation between miR-518 and serum inflammatory factors (hs-CRP, IL-6, and TNF-α), and the relevance between peroxisome proliferator-activated receptor α (PPARα) and serum inflammatory factors. The targeted binding of miR-518 and PPARα was verified using dual-luciferase assay. RESULTS: Serum miR-518 was highly-expressed in GDM and GDM&HDCP patients, but far higher in GDM&HDCP patients. Serum miR-518 level > 1.815 could assist the diagnosis of GDM (81.53% sensitivity and 100% specificity). Serum miR-518 expression was positively-correlated with serum inflammatory factors. miR-518 targeted PPARα and PPARα was lowly-expressed in the serum of GDM and GDM&HDCP patients. PPARα was negatively-linked with serum inflammatory factors. CONCLUSION: High expression of miR-518 assists the diagnosis of GDM and GDM&HDCP, and miR-518 regulates the serum inflammatory factors by inhibiting PPARα.

The Impact of Sex and Gender on Stroke.

Women face a disproportionate burden of stroke mortality and disability. Biologic sex and sociocultural gender both contribute to differences in stroke risk factors, assessment, treatment, and outcomes. There are substantial differences in the strength of association of stroke risk factors, as well as female-specific risk factors. Moreover, there are differences in presentation, response to treatment, and stroke outcomes in women. This review outlines current knowledge of impact of sex and gender on stroke, as well as delineates research gaps and areas for future inquiry.

Protein-creatinine ratio and albumin-creatinine ratio for the diagnosis of significant proteinuria in pregnant women with hypertension: Systematic review and meta-analysis of diagnostic test accuracy.

BACKGROUND: The gold standard for assessment and diagnosis of significant proteinuria in pregnancy has been by 24-hour urine collection and analysis. Determining fast, accurate methods to identify clinically significant proteinuria would aid diagnosis of pre-eclampsia. The objective of this study was to determine the accuracy of spot protein-creatinine ratio (PCR) and albumin-creatinine ratio (ACR) measurements compared with 24-hour urine collection for the identification of clinically significant proteinuria in women with hypertensive disorders of pregnancy. METHODS: Search strategies were developed for electronic databases from inception to 1st October 2020. Data were assessed for methodological quality using the QUADAS-II checklist for risk of bias and quality of the evidence using GRADE. Meta-analysis was performed where there were at least four studies presenting data for the same comparison (test and threshold). This is an update of the review for NICE guideline NG133 (published June 2019) and includes additional data. RESULTS: Twenty-nine studies were included. PCR measurements (28 studies) showed high sensitivity (91%) and specificity (89%) at a threshold of 30 mg/mmol (n = 3577). Higher thresholds (>60 mg/mmol) increased specificity, but reduced sensitivity. At a threshold of PCR 30 mg/mmol, diagnostic accuracy improved for sensitivity and specificity (93% for both) in studies where the first morning void was excluded (n = 1868). Data available (4 studies) for ACR supports ruling out of significant proteinuria at less than 2 mg/mmol, though evidence was limited by paucity of data and wide confidence intervals around the result. CONCLUSIONS: PCR and ACR have high accuracy compared to the gold standard 24-hour urine collection.

Early Pregnancy Atherogenic Profile in a First Pregnancy and Hypertension Risk 2 to 7 Years After Delivery.

Background Cardiovascular risk in young adulthood is an important determinant of lifetime cardiovascular disease risk. Women with adverse pregnancy outcomes (APOs) have increased cardiovascular risk, but the relationship of other factors is unknown. Methods and Results Among 4471 primiparous women, we related first-trimester atherogenic markers to risk of APO (hypertensive disorders of pregnancy, preterm birth, small for gestational age), gestational diabetes mellitus (GDM) and hypertension (130/80 mm Hg or antihypertensive use) 2 to 7 years after delivery. Women with an APO/GDM (n=1102) had more atherogenic characteristics (obesity [34.2 versus 19.5%], higher blood pressure [systolic blood pressure 112.2 versus 108.4, diastolic blood pressure 69.2 versus 66.6 mm Hg], glucose [5.0 versus 4.8 mmol/L], insulin [77.6 versus 60.1 pmol/L], triglycerides [1.4 versus 1.3 mmol/L], and high-sensitivity C-reactive protein [5.6 versus 4.0 nmol/L], and lower high-density lipoprotein cholesterol [1.8 versus 1.9 mmol/L]; P<0.05) than women without an APO/GDM. They were also more likely to develop hypertension after delivery (32.8% versus 18.1%, P<0.05). Accounting for confounders and factors routinely assessed antepartum, higher glucose (relative risk [RR] 1.03 [95% CI, 1.00-1.06] per 0.6 mmol/L), high-sensitivity C-reactive protein (RR, 1.06 [95% CI, 1.02-1.11] per 2-fold higher), and triglycerides (RR, 1.27 [95% CI, 1.14-1.41] per 2-fold higher) were associated with later hypertension. Higher physical activity was protective (RR, 0.93 [95% CI, 0.87-0.99] per 3 h/week). When evaluated as latent profiles, the nonobese group with higher lipids, high-sensitivity C-reactive protein, and insulin values (6.9% of the cohort) had increased risk of an APO/GDM and later hypertension. Among these factors, 7% to 15% of excess RR was related to APO/GDM. Conclusions Individual and combined first-trimester atherogenic characteristics are associated with APO/GDM occurrence and hypertension 2 to 7 years later. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02231398.

Low prevalence of antiannexin A5 antibodies in unprovoked venous thrombosis.

INTRODUCTION: The antiphospholipid syndrome (APS) is characterized by thrombosis or pregnancy morbidity, and the detection in the blood of at least one of three antiphospholipid antibodies (lupus anticoagulant, or anticardiolipin or anti-ß2 -glycoprotein I antibodies). Diagnosing APS is important so that secondary prophylaxis may be administered to reduce risk of recurrent thrombosis and/or pregnancy morbidity. In addition to APS-defining antibodies, there may be additional autoantibodies that have a role in thrombosis and/or pregnancy morbidity. Furthermore, some patients have clinical manifestations highly suggestive of APS but are persistently negative for the APS-defining antibodies ("seronegative APS") and instead, have other autoantibodies. Antiannexin A5 (aANXA5) autoantibodies have been associated with increased risk of thrombosis and pregnancy morbidity; levels are also reportedly higher in patients with venous thrombosis compared with healthy controls. The prevalence of aANXA5 among patients with unprovoked venous thrombosis is not well-documented and determination of the frequency of aANXA5 is the objective of this study. METHODS: We analysed sera from 148 patients with unprovoked venous thrombosis who had undergone routine laboratory testing for the present APS-defining antibodies. RESULTS: aANXA5 IgG and IgM were present in 6% and 1%, respectively. CONCLUSION: Prevalence of these antibodies in unprovoked venous thrombosis is comparable with frequencies reported in healthy individuals and is far lower than the prevalence in women with pregnancy morbidity. This may indicate lack of association with venous thrombosis, however, adequately powered case-control studies will be required to resolve this and prevalence data from this study will assist in the design of such studies.

Maternal cholesterol levels during gestation: boon or bane for the offspring?

An increase in cholesterol levels is perceived during pregnancy and is considered as a normal adaptive response to the development of the fetus. In some pregnancies, excessive increase in total cholesterol with high levels of Low-Density Lipoprotein leads to maladaptation by the fetus to cholesterol demands, resulting in a pathological condition termed as maternal hypercholesterolemia (MH). MH is considered clinically irrelevant and therefore cholesterol levels are not routinely checked during pregnancy, as a consequence of which there is scarce information on its global prevalence in pregnant women. Studies have reported that MH during pregnancy can cause atherogenesis in adults emphasizing the concept of in utero programming of fetus. Moreover, Gestational Diabetes Mellitus, obesity and Polycystic Ovary Syndrome are potential risk factors which strengthen combined pathologies in placenta and fetuses of mothers with MH. However, lack of conclusive evidence on cholesterol transport and underlying programming demand substantial research to develop population-based life style strategies for women in their childbearing years. The current review focuses on the mechanisms and outcomes of MH from existing epidemiological as well as experimental data and presents a detailed insight on this novel risk factor of cardiovascular diseases.

Bleeding and thrombotic risk in pregnant women with Fontan physiology.

BACKGROUND/OBJECTIVES: Pregnancy may potentiate the inherent hypercoagulability of the Fontan circulation, thereby amplifying adverse events. This study sought to evaluate thrombosis and bleeding risk in pregnant women with a Fontan. METHODS: We performed a retrospective observational cohort study across 13 international centres and recorded data on thrombotic and bleeding events, antithrombotic therapies and pre-pregnancy thrombotic risk factors. RESULTS: We analysed 84 women with Fontan physiology undergoing 108 pregnancies, average gestation 33±5 weeks. The most common antithrombotic therapy in pregnancy was aspirin (ASA, 47 pregnancies (43.5%)). Heparin (unfractionated (UFH) or low molecular weight (LMWH)) was prescribed in 32 pregnancies (30%) and vitamin K antagonist (VKA) in 10 pregnancies (9%). Three pregnancies were complicated by thrombotic events (2.8%). Thirty-eight pregnancies (35%) were complicated by bleeding, of which 5 (13%) were severe. Most bleeds were obstetric, occurring antepartum (45%) and postpartum (42%). The use of therapeutic heparin (OR 15.6, 95% CI 1.88 to 129, p=0.006), VKA (OR 11.7, 95% CI 1.06 to 130, p=0.032) or any combination of anticoagulation medication (OR 13.0, 95% CI 1.13 to 150, p=0.032) were significantly associated with bleeding events, while ASA (OR 5.41, 95% CI 0.73 to 40.4, p=0.067) and prophylactic heparin were not (OR 4.68, 95% CI 0.488 to 44.9, p=0.096). CONCLUSIONS: Current antithrombotic strategies appear effective at attenuating thrombotic risk in pregnant women with a Fontan. However, this comes with high (>30%) bleeding risk, of which 13% are life threatening. Achieving haemostatic balance is challenging in pregnant women with a Fontan, necessitating individualised risk-adjusted counselling and therapeutic approaches that are monitored during the course of pregnancy.

Can pregnancy-adapted algorithms avoid diagnostic imaging for pulmonary embolism?

The low prevalence of pulmonary embolism (PE) among pregnant patients presenting with suspected PE implies that most of these patients will be found not have the disease. Given this low prevalence, excluding PE in this population has necessitated the use of sensitive and specific diagnostic imaging, such as computed tomography pulmonary angiography or ventilation-perfusion scanning. Recent studies suggest that a clinical prediction rule with D-dimer testing can also be used to exclude a subset of pregnant patients with suspected PE without the need for diagnostic imaging. The YEARS criteria, which consist of clinical signs and symptoms of deep venous thrombosis, hemoptysis, and PE as the most likely diagnosis (a subjective variable), combined with selective D-dimer levels, seem to safely exclude up to one-third of these patients without imaging. The revised Geneva rule using objective variables, combined with nonpregnancy cutoffs for D-dimer levels, offers some promise, although fewer patients avoided imaging (14%). These recent studies provide evidence in support of radiation avoidance for some patients; however, for most, imaging remains the only option. Future studies should focus on improving the safety and techniques of imaging modalities, in addition to improving the specificity of D-dimer testing and objective prediction rules. Studies assessing patients' and physicians' values, preferences, and risk perceptions are also required to assist clinicians in shared decision making when counseling pregnant patients with suspected PE.

Pregnancy in a healthy population: dynamics of NTproBNP and hs-cTroponin T.

OBJECTIVE: To describe the intraindividual changes of heart biomarker levels during and after pregnancy and to evaluate existing cut-off levels for heart failure or myocardial ischaemia in pregnant women. METHOD: A total of 196 healthy pregnant women were recruited from maternal outpatient clinics and included in the study. Blood samples were obtained on four occasions: at 10-12 gestational weeks (gw), 20-25 gw, after delivery and 6 months postpartum and analysed for N-terminal pro-brain natriuretic peptide (NTproBNP) and high sensitive cardiac troponin T (hs-cTNT). Echocardiography ruled out existing cardiac disease. Estimated glomerular filtration rate (eGFR) was calculated. RESULTS: There were significant changes in NTproBNP between the measurements with the highest NTproBNP at 10-12 gw and the lowest value being at 20-25 gw, (with eGFR being the highest). Hs-cTNT was significantly higher at the peripartum measurement compared with the other measurements (p<0.05). Regardless, the 95th percentile for both biomarkers was below cut-off levels of 300 ng/L for NTproBNP and 14 ng/L for hs-cTNT. There was an association between NTproBNP above the upper limit of normal of 125 ng/L and eGFR (p=0.04) and between hs-cTNT >5.0 ng/L and time from delivery to blood sample (p=0.001) at the peripartum measurement. Both were associated with the use of oxytocin. CONCLUSION: Existing cut-off values for ruling out heart failure (NTproBNP <300 ng/L) and myocardial ischaemia (hs-cTNT <14 ng/L) are applicable during pregnancy and after delivery. Elevated levels mandate further attention on cardiac symptoms and renal function.

Systematic review and meta-analysis of prolactin and iron deficiency in peripartum cardiomyopathy.

OBJECTIVES: We conducted a systematic review and meta-analysis of studies that compared levels of molecular biomarkers in women with peripartum cardiomyopathy (PPCM) to those in healthy pregnant and postpartum women to: (1) assess the evidence for prolactin (PRL) metabolism in PPCM, (2) ascertain the evidence for biomarkers of iron deficiency in PPCM, (3) identify other biomarkers associated with PPCM. METHODS: We searched Medline, Embase, Cumulated Index to Nursing and Allied Health Literature (CINAHL) and the Global Health Library from inception without language restriction for studies that compared biomarkers levels in PPCM cases to healthy controls. Pooled standardised mean difference (SMD) was generated using a random effects model for the difference in levels of biomarkers. RESULTS: Two studies assessed the association of PRL with PPCM, and reported that PPCM cases have higher levels of total PRL. No studies investigated iron metabolism in PPCM. Other biomarkers associated with PPCM included serum levels of natriuretic peptides (SMD=3.77, 95% CI 0.71 to 6.82), albumin (SMD=-0.67, 95% CI -1.01 to -0.32), C-reactive protein (SMD=1.67, 95% CI 0.22 to 3.12), selenium (SMD=-0.73, 95% CI -1.58 to 0.12), cardiac troponins (SMD=1.06, 95% CI 0.33 to 1.80), creatinine (SMD=0.51, 95% CI 0.33 to 0.69), white bloodcells (SMD=0.44, 95 % CI 0.07 to 0.82), haemoglobin (SMD=-0.45, 95% CI -0.64 to-0.26). CONCLUSIONS: More robust molecular studies are needed to explore the association between prolactin and PPCM in human subjects and to determine the extent to which iron deficiency (with or without anaemia) contributes to the risk of PPCM.

Diagnosing Pulmonary Embolism in Pregnancy: Synthesis of Current Guidelines and New Evidence.

Pulmonary embolism (PE) complicates 5.4 per 10 000 pregnancies and remains a significant cause of maternal mortality. Prompt diagnosis and treatment of PE are key to ensuring optimal outcomes, but are not without risks associated with over-testing. Given the paucity of evidence informing PE diagnosis in pregnancy, marked heterogeneity exists among different societies in their recommendations. Here we provide an overview of existing recommendations and novel evidence informing the diagnosis of PE in pregnancy, including the use of d-dimers, the choice of diagnostic imaging modality, and the potential for breast cancer risk among women exposed to ionizing radiation from computed tomography pulmonary angiography (CTPA).

Relevance of the assessment of natriuretic peptide plasma concentrations in hypertensive pregnant women.

Assessment of the plasma concentrations of natriuretic peptides (NPs) is widely used to diagnose and evaluate the progression of cardiac failure, and their potential as markers of preeclampsia (PE) has been examined in recent years. It has been established that plasma concentrations of NPs do not change in the course of normal pregnancy. However, elevated levels of these peptides may have a prognostic value in patients with PE. This study presents information about the relevance of NPs assessment in the evaluation of physiological pregnancy, as well as in pregnancy complicated with arterial hypertension. The most commonly examined NPs is the N-terminal fragment of the brain natriuretic peptide (NT-proBNP), and it may be prognostic marker of PE and other complications of pregnancy.

Pregnancy-induced Cardiovascular Pathologies: Importance of Structural Components and Lipids.

Pregnancy leads to adaptations for maternal and fetal energy needs. The cardiovascular system bears the brunt of the adaptations as the heart and vessels enable nutrient supply to maternal organs facilitated by the placenta to the fetus. The components of the cardiovascular system are critical in the balance between maternal homeostatic and fetus driven homeorhetic regulation. Since lipids intersect maternal cardiovascular function and fetal needs with growth and in stress, factors affecting lipid deposition and mobilization impact risk outcomes. Here, the cardiovascular components and functional derangements associated with cardiovascular pathology in pregnancy, vis-à-vis lipid deposition, mobilization and maternal and/or cardiac and fetal energy needs are detailed. Most reports on the components and associated pathology in pregnancy, are on derangements affecting the extracellular matrix and epicardial fat, followed by the endothelium, vascular smooth muscle, pericytes and myocytes. Targeted studies on all cardiovascular components and pathological outcomes in pregnancy will enhance targeted interventions.

Hypertensive disorders of pregnancy: Strategy to develop clinical peptide biomarkers for more accurate evaluation of the pathophysiological status of this syndrome.

Hypertensive disorders of pregnancy (HDP) is the most common and widely known as serious complication of pregnancy. As this syndrome is a major leading cause of maternal, fetal, and neonatal morbidity/mortality worldwide, many studies have sought to identify candidate molecules as potential disease biomarkers (DBMs) for use in clinical examinations. Accumulating evidence over the past 2 decades that the many proteolytic peptides appear in human humoral fluids, including peripheral blood, in association with an individual's health condition. This review provides the potential utility of peptidomic analysis for monitoring for pathophysiological status in HDP, and presents an overview of current status of peptide quantification technology. Especially, the technical limitations of the methods used for DBM discovery in the blood are discussed.

Angiogenic Marker Prognostic Models in Pregnant Women With Hypertension.

Angiogenic markers such as PlGF (placental growth factor) and sFlt-1 (soluble Fms-like tyrosine kinase-1) have been shown to be useful for predicting adverse outcome in women suspected of having preeclampsia. The aim of the current study was to evaluate the prognostic value of angiogenic markers and maternal risk factors in pregnant women with hypertension. This was a prospective study of pregnancies complicated by preeclampsia, gestational hypertension, or chronic hypertension presenting to 1 of 2 tertiary referral hospitals between May 2013 and May 2018. Maternal characteristics along with blood samples for angiogenic marker analysis were obtained from participants. The primary outcome was delivery related to preeclampsia within 1 and 2 weeks. In total, 302 women with hypertension were included in the study cohort. The baseline model included maternal body mass index, mean arterial pressure, and clinical diagnosis at the time of assessment. The use of sFlt-1/PIGF ratio combined with the baseline model significantly improved the area under the curve values for predicting delivery within a week (0.83 versus 0.88; P=0.025) or in 2 weeks (0.86 versus 0.93; P=0.001) due to preeclampsia-related events in gestational ages <35 weeks. The magnitude of increase in accuracy was 7.9% (-0.5% to 16.4%, posterior probability of increase: 96.7%) for sFlt-1/PlGF ratio. Our results emphasize the additive value of angiogenic biomarkers and the superior performance of a continuous scale of sFlt-1/PlGF ratio in the model. The added utility of angiogenic markers diminishes after 35 weeks' gestation.