Placental severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a specific histiocytic intervillositis. Placental fibrin depositions can decrease the maternal-fetal interface causing fetal distress. Coronavirus disease 2019-related placental inflammation can lead to SARS-CoV-2-associated pediatric inflammatory multisystem syndrome.

We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log 10 increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV—CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences—is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence.

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Heart failure (HF) and chronic kidney disease (CKD) co-exist, and it is estimated that about 50% of HF patients suffer from CKD. Although studies have been performed on the association between CKD and HF with reduced ejection fraction (HFrEF), less is known about the link between CKD and heart failure with preserved ejection fraction (HFpEF). Approximately, 50% of all patients with HF suffer from HFpEF, and this percentage is projected to rise in the coming years. Therapies for HFrEF are long established and considered quite successful. In contrast, clinical trials for treatment of HFpEF have all shown negative or disputable results. This is likely due to the multifactorial character and the lack of pathophysiological knowledge of HFpEF. The typical co-existence of HFpEF and CKD is partially due to common underlying comorbidities, such as hypertension, dyslipidemia and diabetes. Macrovascular changes accompanying CKD, such as hypertension and arterial stiffening, have been described to contribute to HFpEF development. Furthermore, several renal factors have a direct impact on the heart and/or coronary microvasculature and may underlie the association between CKD and HFpEF. These factors include: (1) activation of the renin-angiotensin-aldosterone system, (2) anemia, (3) hypercalcemia, hyperphosphatemia and increased levels of FGF-23, and (4) uremic toxins. This review critically discusses the above factors, focusing on their potential contribution to coronary dysfunction, left ventricular stiffening, and delayed left ventricular relaxation. We further summarize the directions of novel treatment options for HFpEF based on the contribution of these renal drivers.

Background The phosphodiesterase-5 inhibitor (PDE5) sildenafil has emerged as a promising treatment for preeclampsia (PE). However, a sildenafil trial was recently halted due to lack of effect and increased neonatal morbidity. Methods Ex vivo dual-sided perfusion of an isolated cotyledon and wire-myography on chorionic plate arteries were performed to study the effects of sildenafil and the non-selective PDE inhibitor vinpocetine on the response to the NO donor sodium nitroprusside (SNP) under healthy and PE conditions. Ex vivo perfusion was also used to study placental transfer of sildenafil in 6 healthy and 2 PE placentas. Furthermore, placental mRNA and protein levels of eNOS, iNOS, PDE5 and PDE1 were quantified. Findings Sildenafil and vinpocetine significantly enhanced SNP responses in chorionic plate arteries of healthy, but not PE placentas. Only sildenafil acutely decreased baseline tension in arteries of both healthy and PE placentas. At steady state, the foetal-to-maternal transfer ratio of sildenafil was 0·37 ± 0·03 in healthy placentas versus 0·66 and 0·47 in the 2 PE placentas. mRNA and protein levels of PDE5, eNOS and iNOS were comparable in both groups, while PDE1 levels were lower in PE. Interpretation The absence of sildenafil-induced NO potentiation in arteries of PE placentas, combined with the non-PDE-mediated effects of sildenafil and the lack of PDE5 upregulation in PE, argue against sildenafil as the preferred drug of use in PE. Moreover, increased placental transfer of sildenafil in PE might underlie the neonatal morbidity in the STRIDER trial. Fund This study was funded by an mRACE Erasmus MC grant.

(L-)tryptophan is metabolized via the kynurenine pathway into several kynurenine metabolites with distinct functions. Dysfunction of the kynurenine pathway can lead to impairments in vascular regulation, immune regulation, and tolerance. The first and rate limiting enzyme of this pathway, indoleamine 2,3-dioxygenase (IDO), is highly expressed in the placenta and reduced in placentas from complicated pregnancies. IDO is essential during pregnancy, as IDO inhibition in pregnant mice resulted in fetal loss. However, the exact function of placental IDO, as well as its exact placental localization, remain controversial. This review identified that two isoforms of IDO; IDO1 and IDO2, are differently expressed between placental cells, suggesting spatial segregation. Furthermore, this review summarizes how the placental kynurenine pathway is altered in pregnancy complications, including recurrent miscarriage, preterm birth, preeclampsia, and fetal growth restriction. Importantly, we describe that these alterations do not affect maternally circulating metabolite concentrations, suggesting that the kynurenine pathway functions as a local signaling pathway. In the placenta, it is an important source of de novo placental NAD+ synthesis and regulates fetal tryptophan and kynurenine metabolite supply. Therefore, kynurenine pathway interventions might provide opportunities to treat pregnancy complications, and this review discusses how such treatment could affect placental function and pregnancy development.

Introduction In general SARS-CoV-2-infection during pregnancy is not considered to be an increased risk for severe maternal outcomes, but has been associated with an increased risk for fetal distress. So far, there is no direct evidence of intrauterine vertical transmission and the mechanisms leading to the adverse outcomes are not well understood Results An asymptomatic pregnant woman with preterm fetal distress during the COVID19 pandemic was included. We obtained multiple maternal, placental and neonatal swabs, which showed a median viral load in maternal blood, urine, oropharynx, fornix posterior over a period of 6 days was 5.0 log copies /mL. The maternal side of the placenta had a viral load of 4.42 log copies /mL, while the fetal side had 7.15 log copies /mL. Maternal breast milk, feces and all neonatal samples tested negative. Serology of immunoglobulins against SARS-CoV-2 was tested positive in maternal blood, but negative in umbilical cord and neonatal blood. Pathological examination of the placenta included immunohistochemical investigation against SARS-CoV-2 antigen expression in combination with SARS-CoV-2 RNA in situ hybridization and transmission electron microscopy. It showed the presence of SARS-CoV-2 particles with generalized inflammation characterized by histiocytic intervillositis with diffuse perivillous fibrin depositions with damage to the syncytiotrophoblasts. Discussion Placental infection by SARS-CoV-2 lead to fibrin depositions hampering fetal-maternal gas exchange most likely resulted in fetal distress necessitating a premature emergency caesarean section. Postpartum, the neonate showed a clinical presentation resembling a pediatric inflammatory multisystem syndrome including coronary artery ectasia, most likely associated with SARS-CoV-2 (PIMS-TS) for which admittance and care on the Neonatal Intensive Care unit (NICU) was required, despite being negative for SARS-CoV-2. This highlights the need for awareness of adverse fetal and neonatal outcomes during the current COVID-19 pandemic, especially considering that the majority of pregnant women appear asymptomatic.

l -tryptophan induces IDO (indoleamine 2,3-dioxygenase) 1–dependent vasodilation. IDO1 is expressed in placental endothelial cells and downregulated in preeclampsia. Hypothesizing that this may contribute to diminished placental perfusion, we studied l -tryptophan–induced vasodilation in healthy and early-onset preeclampsia placental arteries, focusing on placental kynurenine pathway alterations. Despite IDO1 downregulation, kynurenine pathway metabolite concentrations (measured with ultra-performance liquid chromatography-tandem mass spectrometry) were unaltered in preeclamptic versus healthy placentas. Most likely, this is due to enhanced l -tryptophan uptake, evidenced by increased l -tryptophan levels in preeclamptic placentas. Ex vivo perfused cotyledons from healthy and preeclamptic placentas released similar amounts of l -tryptophan and kynurenine pathway metabolites into the circulations. This release was not altered by adding l -tryptophan in the maternal circulation, suggesting that l -tryptophan metabolites act intracellularly. Maternally applied l -tryptophan did appear in the fetal circulation, confirming placental passage of this essential amino acid. After in vitro incubation of placental arteries with IDO1-upregulating cytokines interferon-γ and tumor necrosis factor-α, l -tryptophan induced vasodilation. This vasodilation was attenuated by both IDO1 and nitric oxide (NO) synthase inhibitors. Despite IDO1 downregulation, l -tryptophan–induced relaxation was enhanced in preeclamptic versus healthy placental arteries. However, cytokine stimulation additionally upregulated the LAT ( l -type amino acid transporter) 1 in preeclamptic placental arteries only. Vasodilation to the lipophilic, transporter independent ethyl ester of l -tryptophan was reduced in preeclamptic versus healthy placental arteries, in agreement with reduced IDO1 expression. In conclusion, l -tryptophan induces IDO1- and NO-dependent relaxation in placental arteries, which is determined by l -tryptophan uptake rather than IDO1 expression. Increased l -tryptophan uptake might compensate for reduced IDO1 expression in preeclamptic placentas.