The present systematic review analyses the role of soluble fms-like tyrosine kinase-1 (sFLT-1) as an indirect biomarker of endothelial dysfunction in sepsis or septic shock from articles published in PubMed between 2010 and March 2022.
A systematic review of studies studying sFLT-1 monitoring in intensive care units in adults with sepsis or septic shock vs. controls for sepsis diagnosis and prognosis has been carried out (PROSPERO CRD42023412929 Registry).
The endothelial dysfunction of sepsis is one of the keys to the development of the disease. VEGF binds to sFLT-1 acting as a competitive inhibitor of VEGF signalling in endothelial cells and thus neutralizes its pro-inflammatory effects. Endothelial dysfunction is reflected in increased sFLT-1 levels. High values of sFLT-1 were used for the differential diagnosis of sepsis versus other inflammatory pathologies, septic shock versus other types of shock, were elevated over time, estimation of disease prognosis, correlation with sepsis severity, organ dysfunction, and mortality prediction.
It is evident that sepsis is based on endothelial dysfunction. sFLT-1 is one of the main biomarkers of microvascular alteration and is a predictive diagnostic and prognostic biomarker.

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.

Pregnancy involves an interplay between maternal and fetal factors affecting changes to maternal anatomy and physiology to support the developing fetus and ensure the well-being of both the mother and offspring. A century of research has provided evidence of the imperative role of the placenta in the development of preeclampsia. Recently, a growing body of evidence has supported the adaptations of the maternal cardiovascular system during normal pregnancy and its maladaptation in preeclampsia. Debate surrounds the roles of the placenta vs the maternal cardiovascular system in the pathophysiology of preeclampsia. We proposed an integrated model of the maternal cardiac-placental-fetal array and the development of preeclampsia, which reconciles the disease phenotypes and their proposed origins, whether placenta-dominant or maternal cardiovascular system-dominant. These phenotypes are sufficiently diverse to define 2 distinct types: preeclampsia Type I and Type II. Type I preeclampsia may present earlier, characterized by placental dysfunction or malperfusion, shallow trophoblast invasion, inadequate spiral artery conversion, profound syncytiotrophoblast stress, elevated soluble fms-like tyrosine kinase-1 levels, reduced placental growth factor levels, high peripheral vascular resistance, and low cardiac output. Type I is more often accompanied by fetal growth restriction, and low placental growth factor levels have a measurable impact on maternal cardiac remodeling and function. Type II preeclampsia typically occurs in the later stages of pregnancy and entails an evolving maternal cardiovascular intolerance to the demands of pregnancy, with a moderately dysfunctional placenta and inadequate blood supply. The soluble fms-like tyrosine kinase-1-placental growth factor ratio may be normal or slightly disturbed, peripheral vascular resistance is low, and cardiac output is high, but these adaptations still fail to meet demand. Emergent placental dysfunction, coupled with an increasing inability to meet demand, more often appears with fetal macrosomia, multiple pregnancies, or prolonged pregnancy. Support for the notion of 2 types of preeclampsia observable on the molecular level is provided by single-cell transcriptomic survey of gene expression patterns across different cell classes. This revealed widespread dysregulation of gene expression across all cell types, and significant imbalance in fms-like tyrosine kinase-1 (FLT1) and placental growth factor, particularly marked in the syncytium of early preeclampsia cases. Classification of preeclampsia into Type I and Type II can inform future research to develop targeted screening, prevention, and treatment approaches.

Several human randomised controlled trials (RCTs) are investigating the effects of statins on pre-eclampsia (PE) and fetal growth restriction (FGR). This cross-species meta-analysis summarises the preclinical evidence of statin use for PE and FGR.
Evaluate the effects of statins on maternal blood pressure (MBP) and birthweight (BW) in pregnancies complicated by PE or FGR.
PubMed and Embase.com were searched on 10 May 2022 using \'statins\' and \'pregnancy\'.
We included RCTs and cohorts with matched control groups as well as animal studies.
The main outcomes were MBP in mmHg and BW in grams. The standardised mean difference (SMD) with a 95% confidence interval (CI) was calculated. Subgroup analyses on species, statin, dose, timing and route of administration were performed if subgroups included at least three studies.
Our data included one human and 12 animal studies. Prenatal administration of statins significantly reduced MBP during pregnancy (SMD  -2.49 mmHg [95% CI -4.26 to -0.71], p = 0.01). There was no significant effect of statins on BW (SMD 0.69 [95% CI -0.65 to 2.03], p = 0.28). Our subgroup analyses showed no effect on MBP of different doses, species or route of administration.
Our cross-species meta-analyses demonstrate that statins only reduce maternal blood pressure in rodent pregnancies complicated by pre-eclampsia or fetal growth restriction and have no effect on birthweight across species. The broad confidence intervals, inconsistent direction of the observed effects across the studies and large risk of bias lead us to conclude that a solid base for further human RCTs is lacking.

BACKGROUND: We aimed to systemically investigate the diagnostic capacity of soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio in fetal growth restriction (FGR).
METHODS: We systematically searched the PubMed, MEDLINE, Cochrane Library, and EMBASE databases for relevant studies from inception to 15 May 2022. All potentially relevant studies were assessed and then pooled.
RESULTS: Eight studies with 339 patients and 5111 controls were included. A sFlt-1/PlGF ratio >33 was demonstrated a predictive value for FGR with a pooled sensitivity of [0.63, 95% confidence interval (CI) = 0.54-0.71], specificity of (0.84, 95% CI = 0.83-0.85), and area under the curve (AUC) of 0.8354. The pooled sensitivity, specificity, and AUC for the sFlt-1/PlGF ratio ≥85 group were 0.79 (95% CI = 0.66-0.89), 0.69 (95% CI = 0.65-0.74), and 0.8197, respectively.
CONCLUSIONS: These findings revealed that the sFlt-1/PlGF ratio could be a potential indicator in predicting FGR and FGR + PE. More studies are needed to support the conclusion.

Coronary heart disease (CHD) and heart failure (HF) produce significant morbidity/mortality but identifying new biomarkers could help in the management of each. In this article, we summarize the molecular regulation and biomarker potential of PIGF and sFlt-1 in CHD and HF. PlGF is elevated during ischemia and some studies have shown PlGF, sFlt-1 or PlGF:sFlt-1 ratio, when used in combination with standard biomarkers, strengthens predictions of outcomes. sFlt-1 and PlGF are elevated in HF with sFlt-1 as a stronger predictor of outcomes. Although promising, we discuss additional study criteria needed to confirm the clinical usefulness of PlGF or sFlt-1 in the detection and management of CHD or HF.

Pre-eclampsia remains a major cause of poor perinatal outcome worldwide. As administering acetylsalicylic acid in a high risk population reduces the risk of PE, it is essential to identify women at risk of PE. Several algorithms for PE risk assessment have been developed. They include maternal factors combined with uterine artery pulsatility index, mean arterial pressure, serum pregnancy-associated plasma protein-A, placental growth factor, and serum soluble fms-like tyrosine kinase-1. Beside PE prophylaxis with acetylsalicylic acid, a proper management of women considered at a high risk of PE is essential. The sFlt-1:PlGF ratio between 20 and 34 + 6 weeks may be used to predict a short-term absence of PE or to predict the risk of PE diagnosis within 4 weeks and a significant shortening of the duration of pregnancy associated with it. The sFlt-1:PlGF ratio may be helpful in deciding about hospitalization or choosing the optimal time for corticosteroid administration in women at risk of PE. It may also help to reduce overall healthcare costs.

Angiogenic biomarkers may be predictive of preeclampsia before clinical symptoms. The objective of this review was to determine the relationship between first and second trimester soluble fms-like tyrosine kinase-1/ placental growth factor (sFlt-1/PlGF) ratio and preeclampsia.
A search algorithm using appropriate medical subject headings was developed. PubMed, EMBASE, and Cochrane were searched for publications from inception to July 4, 2017. Observational studies, including prospective and retrospective cohorts, that measured serum sFlt-1/PlGF ratio at ≤24 weeks\' gestation were included. Study characteristics, study design, timing of blood samples, and outcome data were systematically extracted. Study cohorts were grouped into women with low-risk and high-risk factors for preeclampsia.
Fifteen studies were included for analysis, including 11 779 pregnancies. In studies of women with low-risk features, four subgroups from seven studies demonstrated higher sFlt-1/PlGF ratios in women who developed preeclampsia versus those who did not. In studies of women with high-risk features, six subgroups from nine studies demonstrated a higher sFlt-1/PlGF ratio in women who later developed preeclampsia. Elevated sFlt-1/PlGF ratios were especially seen in women who had early-onset or severe preeclampsia.
The serum sFlt-1/PlGF ratio measured at ≤24 weeks\' gestation may be elevated in select women who later develop preeclampsia, but inconsistently so.