Connecting the Dots: Exploring the Interplay Between Preeclampsia and Peripartum Cardiomyopathy.

Preeclampsia and peripartum cardiomyopathy (PPCM) are significant obstetric problems that can arise during or after pregnancy. Both are known to be causes of maternal mortality and morbidity. Several recent studies have suggested a link between preeclampsia and the pathophysiology of PPCM. However, the common thread that connects the two has yet to be thoroughly and fully articulated. Here, we investigate the complex dynamics of preeclampsia and PPCM in this review. Our analysis focuses mainly on inflammatory and immunological responses, endothelial dysfunction as a shared pathway, and potential genetic predisposition to both diseases. To begin, we will look at how excessive inflammatory and immunological responses can lead to clinical symptoms of both illnesses, emphasizing the role of proinflammatory cytokines and immune cells in modifying vascular and tissue responses. Second, we consider endothelial dysfunction to be a crucial point at which endothelial damage and activation contribute to pathogenesis through increased vascular permeability, vascular dysfunction, and thrombus formation. Finally, we examine recent information suggesting genetic predispositions to preeclampsia and PPCM, such as genetic variants in genes involved in the management of blood pressure, the inflammatory response, and heart structural integrity. With this synergistic study, we seek to encourage more research and creative therapy solutions by emphasizing the need for an interdisciplinary approach to understanding and managing the connection between preeclampsia and PPCM.

The Impact of COVID-19 during Pregnancy on Maternal Hemodynamic Function, Angiogenic Markers and Neonatal Outcome.

Infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) in pregnancy are associated with the development of preeclampsia and fetal growth restriction (FGR). Recently, preeclampsia was linked to impaired maternal hemodynamic function. This retrospective study evaluated singleton pregnancies with COVID-19 during pregnancy and healthy pregnant controls matched for gestational age from November 2020 to March 2022. Non-invasive assessment of maternal hemodynamics by continuous wave Doppler ultrasound measurements (USCOM-1A® Monitor) and oscillometric arterial stiffness (Arteriograph) was performed. Overall, 69 pregnant women were included-23 women after COVID-19 during pregnancy and 46 healthy controls. While two women (8.7%) were admitted to the hospital due to COVID-19-related symptoms, none required intensive care unit admission or non-invasive/invasive ventilation. There were no statistically significant differences in the majority of hemodynamic parameters between the two cohorts. The prevalence of FGR was significantly higher in the COVID-19 during pregnancy group (9.5% vs. healthy controls: 0.0%; p = 0.036), especially in nulliparous women. No difference in angiogenic markers and neonatal outcomes were observed between pregnant women after COVID-19 and healthy controls. In conclusion, no significant differences in hemodynamic parameters or neonatal outcome were observed in women with COVID-19 during pregnancy. However, an increased prevalence of FGR could be described.

The Relationship between the Level of Coagulative Function Hypertensive Disorder Complicating Pregnancy.

BACKGROUND AND AIM: Preeclampsia, a pregnancy complication associated with significant maternal and perinatal mortality and morbidity, has been found to be closely linked to dysfunction in the blood coagulation-fibrinolysis system. However, the relationship between hematologic data and severity and onset time of preeclampsia remains unclear. This study aimed to identify specific hematologic parameters in both preeclamptic and normotensive pregnant women and determine their potential significance in the pathogenesis of preeclampsia. MATERIALS AND METHODS: A total of 112 patients with gestational hypertension disease were divided into two groups: early-onset preeclampsia (32 cases) and late-onset preeclampsia (80 cases). A control group of 82 normotensive pregnant women matched for age and parity was also selected. Blood samples were collected from all participants to test for specific hematologic parameters. RESULTS: Mild and severe preeclampsia were associated with lower hemoglobin level (P = 0.01 and P = 0.03, respectively), higher mean platelet volume (P = 0.01 and P = 0.01, respectively) and fibrinogen (P = 0.01 and P = 0.01, respectively), and shorter prothrombin time (P = 0.02 and P = 0.01, respectively) and activated partial thromboplastin time (P = 0.01 and P = 0.02, respectively). CONCLUSION: These findings have provided evidence on the hematologic coagulative actors in the pathogenesis and severity of preeclampsia.

Relationship between proteinuria and changes in antepartum and postpartum choroidal thickness in patients with pre-eclampsia.

Pre-eclampsia (PE) is a hypertensive disorder characterised by systemic vascular resistance and endothelial dysfunction. It is known to influence choroidal thickness (CT). No previous studies have explored the antepartum and postpartum changes in CT with respect to the protein-creatinine ratio (PCR), a measure of proteinuria that is a clinical hallmark of PE. This study evaluated the correlations between antepartum and postpartum CT and the PCR in patients with PE. In this retrospective study, sixty-six eyes (66 patients) were analysed. The patients were divided into two groups according to the median PCR value (2.36 mg/mg): low PCR group (< 2.36 mg/mg) and high PCR group (≥ 2.36 mg/mg). Ophthalmologic clinical data were collected and assessed. We observed higher antepartum CT and higher mean arterial pressure in high PCR group than in low PCR group. Moreover, postpartum CT decreased significantly in high PCR group. In the multivariate analysis, CT changes were correlated with antepartum CT and antepartum PCR after logarithm transformation. In conclusion, a greater decrease in CT was observed in high PCR group than in low PCR group. Further, the antepartum PCR showed a correlation with the extent of CT reduction.

Stroke in Pregnancy and Preeclampsia: Effect of Low-Dose Aspirin Treatment on Collateral Flow Velocity and Cerebral Blood Flow Autoregulation During Ischemia in Rats.

BACKGROUND: Experimental preeclampsia (ePE) has been shown to have worsened outcome from stroke. We investigated the effect of low-dose aspirin, known to prevent preeclampsia, on stroke hemodynamics and outcome, and the association between the vasoconstrictor and vasodilator cyclooxygenase products thromboxane A2 and prostacyclin. METHODS AND RESULTS: Middle cerebral artery occlusion was performed for 3 hours with 1 hour of reperfusion in normal pregnant rats on day 20 of gestation and compared with ePE treated with vehicle or low-dose aspirin (1.5 mg/kg per day). Multisite laser Doppler was used to measure changes in cerebral blood flow to the core middle cerebral artery and collateral vascular territories. After 30 minutes occlusion, phenylephrine was infused to increase blood pressure and assess cerebral blood flow autoregulation. Infarct and edema were measured using 2,3,5-triphenyltetrazolium chloride staining. Plasma levels of thromboxane A2, prostacyclin, and inflammatory markers in plasma and cyclooxygenase levels in cerebral arteries were measured. ePE had increased infarction compared with normal pregnant rats (P<0.05) that was reduced by aspirin (P<0.001). ePE also had intact cerebral blood flow autoregulation and reduced collateral perfusion during induced hypertension that was also prevented by aspirin. Aspirin increased prostacyclin in ePE (P<0.05) without reducing thromboxane B2, metabolite of thromboxane A2, or 8-isoprostane-prostaglandin-2α, a marker of lipid peroxidation. There were no differences in cyclooxygenase levels in cerebral arteries between groups. CONCLUSIONS: Low-dose aspirin in ePE reduced infarction that was associated with increased vasodilator prostacyclin and improved collateral perfusion during induced hypertension. The beneficial effect of aspirin on the brain and cerebral circulation is likely multifactorial and worth further study.

Vascular contraction of umbilical arteries of pregnant women with preeclampsia.

Objective: Potassium channels have an important role in the vascular adaptation during pregnancy and a reduction in the expression of adenosine triphosphate-sensitive potassium channels (Katp) has been linked to preeclampsia. Activation of Katp induces vasodilation; however, no previous study has been conducted to evaluate the effects of the inhibition of these channels in the contractility of preeclamptic arteries. Glibenclamide is an oral antihyperglycemic agent that inhibits Katp and has been widely used in vascular studies. Methods: To investigate the effects of the inhibition of Katp, umbilical arteries of preeclamptic women and women with healthy pregnancies were assessed by vascular contractility experiments, in the presence or absence of glibenclamide. The umbilical arteries were challenged with cumulative concentrations of potassium chloride (KCl) and serotonin. Results: There were no differences between the groups concerning the maternal age and gestational age of the patients. The percentage of smokers, caucasians and primiparae per group was also similar. On the other hand, blood pressure parameters were elevated in the preeclamptic group. In addition, the preeclamptic group presented a significantly higher body mass index. The newborns of both groups presented similar APGAR scores and weights. Conclusion: In the presence of glibenclamide, there was an increase in the KCl-induced contractions only in vessels from the PE group, showing a possible involvement of these channels in the disorder.

Placental Methylglyoxal in Preeclampsia: Vascular and Biomarker Implications.

BACKGROUND: Preeclampsia is a multifaceted syndrome that includes maternal vascular dysfunction. We hypothesize that increased placental glycolysis and hypoxia in preeclampsia lead to increased levels of methylglyoxal (MGO), consequently causing vascular dysfunction. METHODS: Plasma samples and placentas were collected from uncomplicated and preeclampsia pregnancies. Uncomplicated placentas and trophoblast cells (BeWo) were exposed to hypoxia. The reactive dicarbonyl MGO and advanced glycation end products (Nε-(carboxymethyl)lysine [CML], Nε-(carboxyethyl)lysine [CEL], and MGO-derived hydroimidazolone [MG-H]) were quantified using liquid chromatography-tandem mass spectrometry. The activity of GLO1 (glyoxalase-1), that is, the enzyme detoxifying MGO, was measured. The impact of MGO on vascular function was evaluated using wire/pressure myography. The therapeutic potential of the MGO-quencher quercetin and mitochondrial-specific antioxidant mitoquinone mesylate (MitoQ) was explored. RESULTS: MGO, CML, CEL, and MG-H2 levels were elevated in preeclampsia-placentas (+36%, +36%, +25%, and +22%, respectively). Reduced GLO1 activity was observed in preeclampsia-placentas (-12%) and hypoxia-exposed placentas (-16%). Hypoxia-induced MGO accumulation in placentas was mitigated by the MGO-quencher quercetin. Trophoblast cells were identified as the primary source of MGO. Reduced GLO1 activity was also observed in hypoxia-exposed BeWo cells (-26%). Maternal plasma concentrations of CML and the MGO-derived MG-H1 increased as early as 12 weeks of gestation (+16% and +17%, respectively). MGO impaired endothelial barrier function, an effect mitigated by MitoQ, and heightened vascular responsiveness to thromboxane A2. CONCLUSIONS: This study reveals the accumulation of placental MGO in preeclampsia and upon exposure to hypoxia, demonstrates how MGO can contribute to vascular impairment, and highlights plasma CML and MG-H1 levels as promising early biomarkers for preeclampsia.

Both endothelial mineralocorticoid receptor expression and hyperleptinemia are required for clinical characteristics of placental ischemia in mice.

One of the initiating events in preeclampsia (PE) is placental ischemia. Rodent models of placental ischemia do not present with vascular endothelial dysfunction, a hallmark of PE. We previously demonstrated a role for leptin in endothelial dysfunction in pregnancy in the absence of placental ischemia. We hypothesized that placental ischemia requires hyperleptinemia and endothelial mineralocorticoid receptor (ECMR) expression to induce PE-associated endothelial dysfunction in pregnant mice. We induced placental ischemia via the reduced uterine perfusion pressure (RUPP) procedure in pregnant ECMR-intact (ECMR+/+) and ECMR deletion (ECMR-/-) mice at gestational day (GD) 13. ECMR+/+ RUPP pregnant mice also received concurrent leptin infusion via miniosmotic pump (0.9 mg/kg/day). RUPP increased blood pressure via radiotelemetry and decreased fetal growth in ECMR+/+ pregnant mice. Both increases in blood pressure and reduced fetal growth were abolished in RUPP ECMR-/- mice. Placental ischemia did not decrease endothelial-dependent relaxation to acetylcholine (ACh) but increased phenylephrine (Phe) contraction in mesenteric arteries of pregnant mice, which was ablated by ECMR deletion. Addition of leptin to RUPP mice significantly reduced ACh relaxation in ECMR+/+ pregnant mice, accompanied by an increase in soluble FMS-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PLGF) ratio. In conclusion, our data indicate that high leptin levels drive endothelial dysfunction in PE and that ECMR is required for clinical characteristics of hypertension and fetal growth restriction in placental ischemia PE. Collectively, we show that both ECMR and leptin play a role to mediate PE.NEW & NOTEWORTHY Leptin is a key feature of preeclampsia that initiates vascular endothelial dysfunction in preeclampsia characterized by placental ischemia. Endothelial mineralocorticoid receptor (ECMR) deletion in placental ischemia protects pregnant mice from elevations in blood pressure and fetal growth restriction in pregnancy. Increases in leptin production mediate the key pathological feature of endothelial dysfunction in preeclampsia in rodents. ECMR activation contributes to the increase in blood pressure and fetal growth restriction in preeclampsia.

Reduced uterine perfusion pressure as a model for preeclampsia and fetal growth restriction in murine: a systematic review and meta-analysis.

The reduced uterine perfusion pressure (RUPP) model is frequently used to study preeclampsia and fetal growth restriction. An improved understanding of influential factors might improve reproducibility and reduce animal use considering the variability in RUPP phenotype. We performed a systematic review and meta-analysis by searching Medline and Embase (until 28 March, 2023) for RUPP studies in murine. Primary outcomes included maternal blood pressure (BP) or proteinuria, fetal weight or crown-rump length, fetal reabsorptions, or antiangiogenic factors. We aimed to identify influential factors by meta-regression analysis. We included 155 studies. Our meta-analysis showed that the RUPP procedure results in significantly higher BP (MD = 24.1 mmHg; [22.6; 25.7]; n = 148), proteinuria (SMD = 2.3; [0.9; 3.8]; n = 28), fetal reabsorptions (MD = 50.4%; [45.5; 55.2]; n = 42), circulating soluble FMS-like tyrosine kinase-1 (sFlt-1) (SMD = 2.6; [1.7; 3.4]; n = 34), and lower fetal weight (MD = -0.4 g; [-0.47; -0.34]; n = 113. The heterogeneity (variability between studies) in primary outcomes appeared ≥90%. Our meta-regression identified influential factors in the method and time point of BP measurement, randomization in fetal weight, and type of control group in sFlt-1. The RUPP is a robust model considering the evident differences in maternal and fetal outcomes. The high heterogeneity reflects the observed variability in phenotype. Because of underreporting, we observed reporting bias and a high risk of bias. We recommend standardizing study design by optimal time point and method chosen for readout measures to limit the variability. This contributes to improved reproducibility and thereby eventually improves the translational value of the RUPP model.

Blood pressure responses to handgrip exercise but not apnea or mental stress are enhanced in women with a recent history of preeclampsia.

Preeclampsia is a risk factor for future cardiovascular diseases. However, the mechanisms underlying this association remain unclear, limiting effective prevention strategies. Blood pressure responses to acute stimuli may reveal cardiovascular dysfunction not apparent at rest, identifying individuals at elevated cardiovascular risk. Therefore, we compared blood pressure responsiveness with acute stimuli between previously preeclamptic (PPE) women (34 ± 5 yr old, 13 ± 6 mo postpartum) and women following healthy pregnancies (Ctrl; 29 ± 3 yr old, 15 ± 4 mo postpartum). Blood pressure (finger photoplethysmography calibrated to manual sphygmomanometry-derived values; PPE: n = 12, Ctrl: n = 12) was assessed during end-expiratory apnea, mental stress, and isometric handgrip exercise protocols. Integrated muscle sympathetic nerve activity (MSNA) was assessed in a subset of participants (peroneal nerve microneurography; PPE: n = 6, Ctrl: n = 8). Across all protocols, systolic blood pressure (SBP) was higher in PPE than Ctrl (main effects of group all P < 0.05). Peak changes in SBP were stressor specific: peak increases in SBP were not different between PPE and Ctrl during apnea (8 ± 6 vs. 6 ± 5 mmHg, P = 0.32) or mental stress (9 ± 5 vs. 4 ± 7 mmHg, P = 0.06). However, peak exercise-induced increases in SBP were greater in PPE than Ctrl (11 ± 5 vs. 7 ± 7 mmHg, P = 0.04). MSNA was higher in PPE than Ctrl across all protocols (main effects of group all P < 0.05), and increases in peak MSNA were greater in PPE than Ctrl during apnea (44 ± 6 vs. 27 ± 14 burst/100 hb, P = 0.04) and exercise (25 ± 8 vs. 13 ± 11 burst/100 hb, P = 0.01) but not different between groups during mental stress (2 ± 3 vs. 0 ± 5 burst/100 hb, P = 0.41). Exaggerated pressor and sympathetic responses to certain stimuli may contribute to the elevated long-term risk for cardiovascular disease in PPE.NEW & NOTEWORTHY Women with recent histories of preeclampsia demonstrated higher systolic blood pressures across sympathoexcitatory stressors relative to controls. Peak systolic blood pressure reactivity was exacerbated in previously preeclamptic women during small muscle-mass exercises, although not during apneic or mental stress stimuli. These findings underscore the importance of assessing blood pressure control during a variety of experimental conditions in previously preeclamptic women to elucidate mechanisms that may contribute to their elevated cardiovascular disease risk.

Left Atrial Mechanics Following Preeclamptic Pregnancy.

BACKGROUND: Preterm preeclampsia is a pregnancy complication associated with myocardial dysfunction and premature cardiovascular disease morbidity and mortality. Left atrial (LA) strain is a noninvasive index of left ventricular end diastolic pressure and an early marker of heart failure risk. This study aimed to evaluate LA strain during the postpartum period in participants with and without preterm preeclampsia and to assess whether this varied in the presence of hypertension, cardiac dysfunction or both. METHODS: In this longitudinal cohort study, 321 women from 28 hospitals with preterm preeclampsia (cases) underwent cardiovascular assessment 6 months postpartum. This is a secondary analysis of the PHOEBE study (ISRCTN01879376). An uncomplicated pregnancy control group (n=30) was recruited from a single center for comparison. A full cross-sectional transthoracic echocardiogram was performed, and from these images, the myocardial strain of the left atrium, including reservoir, conduit, and contractile strain, as well as LA stiffness, were calculated. RESULTS: At 6 months postpartum, compared with controls, prior preeclampsia was associated with a significantly attenuated LA reservoir, conduit, and contractile strain, as well as increased LA stiffness (all P<0.001). LA strain was further reduced in preeclamptic women who had and had not developed hypertension, systolic, or diastolic dysfunction at 6 months postpartum (all P<0.05). CONCLUSIONS: LA mechanics were significantly attenuated at 6 months postpartum in participants with preterm preeclampsia, whether or not they remained hypertensive or had evidence of ventricular dysfunction. Further studies are needed to determine whether postnatal LA strain may identify women at greater risk for future cardiovascular disease.

Citral relaxes umbilical vessels of normotensive and preeclamptic parturients.

INTRODUCTION: Citral is a low-toxicity monoterpene that has a vasodilator effect on various smooth muscles, and The present study aimed to evaluate its vasorelaxant effect on umbilical vessels of normotensive parturients (NTP) and with preeclampsia parturients (PEP). METHOD: Segments of human umbilical artery (HUA) and vein (HUV) of NTP or PEP were mounted in a bath to record the force of contraction, under tension of 3.0 gf and contracted with the contracting agents: K+ (60 mM), 5 -HT (10 µM) and Ba2+ (1-30 mM). Next, the effect of citral (1-3000 µM) on these contractions and on basal tone was evaluated. RESULTS: In HUA and HUV, citral (1-1000 µM), in NTP condition, inhibited contractions evoked by K+ (IC50 of 413.5 and 271.3, respectively) and by 5-HT (IC50 of 164.8 and 574.3). In the PEP condition, in HUA and HUV, citral also inhibited the contractions evoked by K+ (IC50 of 363.3 and 218.3, respectively) and 5-HT (IC50 of 432.1 and 520.4). At a concentration of 1000 µM, citral completely or almost completely (>90 %) inhibited all contractions. At a concentration of 100-1000 µM, citral, in general, was already able to reduce the contraction induced by 1-3 mM Ba2+ in both AUH and VUH, under NTP and PEP conditions. DISCUSSION: Citral has been shown to be an effective HUA and HUV vasodilator in NTP and PEP. As its toxicity is low, it suggests that this substance can be considered a potential therapeutic agent.

Sympathetic Neurofunction Testing in Gestational Hypertension and Relationship with Developing Preeclampsia and Eclampsia: Real-world Evidences from Clinical Pharmacology Clinics.

BACKGROUND: Gestational hypertension carries a high-risk for adverse maternal and fetal outcomes, and it can also develop into preeclampsia. A relative decrease in parasympathetic and increase in sympathetic activity has been seen in normal pregnancy which returns to baseline after delivery. The present study aimed to detect any abnormality in sympathetic neurofunction in gestational hypertension and to identify its possible association with the development of preeclampsia/eclampsia. METHODS: A prospective, observational study was carried out among gestational hypertensive patients between 24 and 26 weeks of gestation, who were sent to clinical pharmacology clinics for autonomic neurofunction testing, along with their 24-hour urinary protein testing reports. Preisometric handgrip (IHG) and post-IHG differences in diastolic blood pressure (DBP) were noted. The association between Δ DBP and the development of eclampsia/preeclampsia was probed. RESULTS: A total of 52 pregnancy-induced hypertension (PIH) participants, both multigravida (n = 15) and primigravida (n = 37) were included in one arm (PIH arm), and 52 matched (age and gravida) pregnant women, those do not have PIH included in another arm for comparative analysis. On comparing the PIH arm and normal arm, prehand grip DBP (p ≤ 0.0001), posthand grip DBP, and Δ DBP were significantly higher in the PIH arm. Correlation between Δ DBP and 24 hours' proteinuria was observed in the PIH arm, with a significant positive correlation. CONCLUSION: A high-rise in DBP post-IHG exercise is associated with gestational hypertensive mothers and this rise is strongly correlated with the development of preeclampsia and eclampsia, which suggests that addressing sympathetic hyperactivity could be a potential area to target therapeutics while managing gestational hypertension.

Machine Learning Algorithms Versus Classical Regression Models in Pre-Eclampsia Prediction: A Systematic Review.

PURPOSE OF REVIEW: Machine learning (ML) approaches are an emerging alternative for healthcare risk prediction. We aimed to synthesise the literature on ML and classical regression studies exploring potential prognostic factors and to compare prediction performance for pre-eclampsia. RECENT FINDINGS: From 9382 studies retrieved, 82 were included. Sixty-six publications exclusively reported eighty-four classical regression models to predict variable timing of onset of pre-eclampsia. Another six publications reported purely ML algorithms, whilst another 10 publications reported ML algorithms and classical regression models in the same sample with 8 of 10 findings that ML algorithms outperformed classical regression models. The most frequent prognostic factors were age, pre-pregnancy body mass index, chronic medical conditions, parity, prior history of pre-eclampsia, mean arterial pressure, uterine artery pulsatility index, placental growth factor, and pregnancy-associated plasma protein A. Top performing ML algorithms were random forest (area under the curve (AUC) = 0.94, 95% confidence interval (CI) 0.91-0.96) and extreme gradient boosting (AUC = 0.92, 95% CI 0.90-0.94). The competing risk model had similar performance (AUC = 0.92, 95% CI 0.91-0.92) compared with a neural network. Calibration performance was not reported in the majority of publications. ML algorithms had better performance compared to classical regression models in pre-eclampsia prediction. Random forest and boosting-type algorithms had the best prediction performance. Further research should focus on comparing ML algorithms to classical regression models using the same samples and evaluation metrics to gain insight into their performance. External validation of ML algorithms is warranted to gain insights into their generalisability.

Association Between Preeclampsia and Blood Pressure in Offspring: A Systematic Review and Meta-Analysis.

PURPOSE OF REVIEW: Pregnancy-induced preeclampsia is a severe pregnancy complication and preeclampsia has been associated with an increased risk of chronic hypertension for offspring. However, the magnitude of the overall effect of exposure to preeclampsia in pregnancy on blood pressure (BP) in offspring is unknown. This systematic review and meta-analysis was sought to systematically assess the effects of preeclampsia on the BP of the offspring. RECENT FINDINGS: Of 2550 publications identified, 23 studies were included. The meta-analysis indicated that preeclampsia increases the potential risk of hypertension in offspring. Systolic blood pressure (SBP) was 2.0 mm Hg (95% CI: 1.2, 2.8) and diastolic blood pressure (DBP) was 1.4 mm Hg (95% CI: 0.9, 1.9) higher in offspring exposed to pre-eclampsia in utero, compared to those born to normotensive mothers. The correlations were similar in stratified analyses of children and adolescents by sex, geographic area, ages, and gestational age. During childhood and young adulthood, the offspring of pregnant women with preeclampsia are at an increased risk of high BP. It is crucial to monitor their BP.

Coronary Microvascular Function Following Severe Preeclampsia.

BACKGROUND: Preeclampsia is a pregnancy-specific hypertensive disorder associated with an imbalance in circulating proangiogenic and antiangiogenic proteins. Preclinical evidence implicates microvascular dysfunction as a potential mediator of preeclampsia-associated cardiovascular risk. METHODS: Women with singleton pregnancies complicated by severe antepartum-onset preeclampsia and a comparator group with normotensive deliveries underwent cardiac positron emission tomography within 4 weeks of delivery. A control group of premenopausal, nonpostpartum women was also included. Myocardial flow reserve, myocardial blood flow, and coronary vascular resistance were compared across groups. sFlt-1 (soluble fms-like tyrosine kinase receptor-1) and PlGF (placental growth factor) were measured at imaging. RESULTS: The primary cohort included 19 women with severe preeclampsia (imaged at a mean of 15.3 days postpartum), 5 with normotensive pregnancy (mean, 14.4 days postpartum), and 13 nonpostpartum female controls. Preeclampsia was associated with lower myocardial flow reserve (ß, -0.67 [95% CI, -1.21 to -0.13]; P=0.016), lower stress myocardial blood flow (ß, -0.68 [95% CI, -1.07 to -0.29] mL/min per g; P=0.001), and higher stress coronary vascular resistance (ß, +12.4 [95% CI, 6.0 to 18.7] mm Hg/mL per min/g; P=0.001) versus nonpostpartum controls. Myocardial flow reserve and coronary vascular resistance after normotensive pregnancy were intermediate between preeclamptic and nonpostpartum groups. Following preeclampsia, myocardial flow reserve was positively associated with time following delivery (P=0.008). The sFlt-1/PlGF ratio strongly correlated with rest myocardial blood flow (r=0.71; P<0.001), independent of hemodynamics. CONCLUSIONS: In this exploratory cross-sectional study, we observed reduced coronary microvascular function in the early postpartum period following preeclampsia, suggesting that systemic microvascular dysfunction in preeclampsia involves coronary microcirculation. Further research is needed to establish interventions to mitigate the risk of preeclampsia-associated cardiovascular disease.

The "Preeclampsia and Hypertension Target Treatment" study: a multicenter prospective study to evaluate the effectiveness of the antihypertensive therapy based on maternal hemodynamic findings.

BACKGROUND: Despite major advances in the pharmacologic treatment of hypertension in the nonpregnant population, treatments for hypertension in pregnancy have remained largely unchanged over the years. There is recent evidence that a more adequate control of maternal blood pressure is achieved when the first given antihypertensive drug is able to correct the underlying hemodynamic disorder of the mother besides normalizing the blood pressure values. OBJECTIVE: This study aimed to compare the blood pressure control in women receiving an appropriate or inappropriate antihypertensive therapy following the baseline hemodynamic findings. STUDY DESIGN: This was a prospective multicenter study that included a population of women with de novo diagnosis of hypertensive disorders of pregnancy. A noninvasive assessment of the following maternal parameters was performed on hospital admission via Ultrasound Cardiac Output Monitor before any antihypertensive therapy was given: cardiac output, heart rate, systemic vascular resistance, and stroke volume. The clinician who prescribed the antihypertensive therapy was blinded to the hemodynamic evaluation and used as first-line treatment a vasodilator (nifedipine or alpha methyldopa) or a beta-blocker (labetalol) based on his preferences or on the local protocols. The first-line pharmacologic treatment was retrospectively considered hemodynamically appropriate in either of the following circumstances: (1) women with a hypodynamic profile (defined as low cardiac output [≤5 L/min] and/or high systemic vascular resistance [≥1300 dynes/second/cm2]) who were administered oral nifedipine or alpha methyldopa and (2) women with a hyperdynamic profile (defined as normal or high cardiac output [>5 L/min] and/or low systemic vascular resistances [<1300 dynes/second/cm2]) who were administered oral labetalol. The primary outcome of the study was to compare the occurrence of severe hypertension between women treated with a hemodynamically appropriate therapy and women treated with an inappropriate therapy. RESULTS: A total of 152 women with hypertensive disorders of pregnancy were included in the final analysis. Most women displayed a hypodynamic profile (114 [75.0%]) and received a hemodynamically appropriate treatment (116 [76.3%]). The occurrence of severe hypertension before delivery was significantly lower in the group receiving an appropriate therapy than in the group receiving an inappropriately treated (6.0% vs 19.4%, respectively; P=.02). Moreover, the number of women who achieved target values of blood pressure within 48 to 72 hours from the treatment start was higher in the group who received an appropriate treatment than in the group who received an inappropriate treatment (70.7% vs 50.0%, respectively; P=.02). CONCLUSION: In pregnant individuals with de novo hypertensive disorders of pregnancy, a lower occurrence of severe hypertension was observed when the first-line antihypertensive agent was tailored to the correct maternal hemodynamic profile.

The Pathophysiological, Genetic, and Hormonal Changes in Preeclampsia: A Systematic Review of the Molecular Mechanisms.

Preeclampsia, a serious complication of pregnancy, involves intricate molecular and cellular mechanisms. Fetal microchimerism, where fetal cells persist within maternal tissues and in circulation, acts as a mechanistic link between placental dysfunction and maternal complications in the two-stage model of preeclampsia. Hormones, complements, and cytokines play pivotal roles in the pathophysiology, influencing immune responses, arterial remodeling, and endothelial function. Also, soluble HLA-G, involved in maternal-fetal immune tolerance, is reduced in preeclampsia. Hypoxia-inducible factor 1-alpha (Hif-α) dysregulation leads to placental abnormalities and preeclampsia-like symptoms. Alterations in matrix metalloproteinases (MMPs), endothelins (ETs), chemokines, and cytokines contribute to defective trophoblast invasion, endothelial dysfunction, and inflammation. Preeclampsia's genetic complexity includes circRNAs, miRNAs, and lncRNAs. CircRNA_06354 is linked to early-onset preeclampsia by influencing trophoblast invasion via the hsa-miR-92a-3p/VEGF-A pathway. The dysregulation of C19MC, especially miR-519d and miR-517-5p, affects trophoblast function. Additionally, lncRNAs like IGFBP1 and EGFR-AS1, along with protein-coding genes, impact trophoblast regulation and angiogenesis, influencing both preeclampsia and fetal growth. Besides aberrations in CD31+ cells, other potential biomarkers such as MMPs, soluble HLA-G, and hCG hold promise for predicting preeclampsia and its complications. Therapeutic interventions targeting factors such as peroxisome PPAR-γ and endothelin receptors show potential in mitigating preeclampsia-related complications. In conclusion, preeclampsia is a complex disorder with a multifactorial etiology and pathogenesis. Fetal microchimerism, hormones, complements, and cytokines contribute to placental and endothelial dysfunction with inflammation. Identifying novel biomarkers and therapeutic targets offers promise for early diagnosis and effective management, ultimately reducing maternal and fetal morbidity and mortality. However, further research is warranted to translate these findings into clinical practice and enhance outcomes for at-risk women.