Acute Atherosis Lesions at the Fetal-Maternal Border: Current Knowledge and Implications for Maternal Cardiovascular Health

Decidua basalis, the endometrium of pregnancy, is an important interface between maternal and fetal tissues, made up of both maternal and fetal cells. Acute atherosis is a uteroplacental spiral artery lesion. These patchy arterial wall lesions containing foam cells are predominantly found in the decidua basalis, at the tips of the maternal arteries, where they feed into the placental intervillous space. Acute atherosis is prevalent in preeclampsia and other obstetric syndromes such as fetal growth restriction. Causal factors and effects of acute atherosis remain uncertain. This is in part because decidua basalis is challenging to sample systematically and in large amounts following delivery. We summarize our decidua basalis vacuum suction method, which facilitates tissue-based studies of acute atherosis. We also describe our evidence-based research definition of acute atherosis. Here, we comprehensively review the existing literature on acute atherosis, its underlying mechanisms and possible short- and long-term effects. We propose that multiple pathways leading to decidual vascular inflammation may promote acute atherosis formation, with or without poor spiral artery remodeling and/or preeclampsia. These include maternal alloreactivity, ischemia-reperfusion injury, preexisting systemic inflammation, and microbial infection. The concept of acute atherosis as an inflammatory lesion is not novel. The lesions themselves have an inflammatory phenotype and resemble other arterial lesions of more extensively studied etiology. We discuss findings of concurrently dysregulated proteins involved in immune regulation and cardiovascular function in women with acute atherosis. We also propose a novel hypothesis linking cellular fetal microchimerism, which is prevalent in women with preeclampsia, with acute atherosis in pregnancy and future cardiovascular and neurovascular disease. Finally, women with a history of preeclampsia have an increased risk of premature cardiovascular disease. We review whether presence of acute atherosis may identify women at especially high risk for premature cardiovascular disease.

Atherosis of trophoblast type: A specific form of decidual vasculopathy distinct from atherosis of macrophage type

Background: There are three types of decidual vasculopathy, namely, acute atherosis, fibrinoid medial necrosis and mural arterial hyerptrophy. Persistence of vascular trophoblasts is also known to be related to maternal vascular malperfusion, but detailed study is lacking. Material and methods: A total 1017 placentas from 2021 were collected with clinical, neonatal and placental information, and routine placental pathology examination was performed. Decidual vasculopathy was classified based on the new classification scheme including atherosis of macrophage type atherosis of trophoblast type, fibrinoid medial necrosis, mural arterial hypertrophy and mixed type vasculopathy. The significance of these morphologic changes were examined based on the clinical, neonatal and placental pathology features. Results: Decidual vasculopathy is classified as classic type, mural hypertrophy and mixed type. Classic type vasculopathy is further separated as atherosis and fibrinoid medial necrosis. Atherosis is defined as atherosis of macrophage type and atherosis of trophoblast type. Each category of decidual vasculopathy was evaluated in association with maternal, neonatal and placental pathologic findings. Atherosis of macrophage type and mixed type vasculopathy showed statistically significant association with preeclampsia/pregnancy induced hypertension, low birth weight and low placental weight. Atherosis of trophoblast type was associated with lower placental weight but not with specific clinical features. There is no neonatal sex dimorphism in decidual vasculopathy. Conclusion: Atherosis of trophoblast type is a distinct pathologic feature in late pregnancy, and it is associated with lower placental weight. New classification of decidual vasculopathy helps with better stratification and categorization of placental maternal vascular abnormalities.

Multiplex Analysis of Circulating Maternal Cardiovascular Biomarkers Comparing Preeclampsia Subtypes

Preeclampsia, a hypertensive pregnancy disorder, links to increased long-term maternal cardiovascular disease (CVD). The risk is further increased with early-onset preeclampsia (EPE) and delivery of a growth-restricted child. We hypothesized that circulating biomarkers associated with CVD risk differed between preeclampsia subtypes and controls. We compared EPE; n=37, delivery <week 34, late-onset preeclampsia (LPE); n=29, delivery ≥week 34, and normotensive controls (n=49) using Olink Proseek multiplex CVD I assay (targeting 92 biomarkers). We stratified analysis to uteroplacental spiral artery acute atherosis presence in preeclampsia patients, sharing morphological similarities with atherosclerosis. We found 47 CVD-related biomarkers differing between the groups, 42 markers between normotensive controls and EPE, 28 markers between normotensive controls and LPE, and 9 markers between EPE and LPE. Among these 9 markers, ST2 (ST2 protein), MMP (matrix metalloproteinase) 1, MMP3, and fractalkine (CX3CL1) were uniquely dysregulated in EPE. Principal component (PC) analysis of the differing markers identified 4 clusters (named PC1–PC4) that largely separated the preeclampsia and control groups as well as pregnancies with low and high circulating PlGF (placental growth factor). The combination of the single markers PlGF, ST2, MMP1, MMP3, and CX3CL1 had a high discriminatory property to differentiate between EPE and LPE. Preeclampsia with acute atherosis or with fetal growth restriction could be differentiated by Olink biomarkers as compared with preeclampsia without these features. We identified specific CVD-related biomarkers in pregnancy depending on preeclampsia subtypes and uteroplacental acute atherosis. Assessment of these pregnancy measured biomarkers’ relation to long-term cardiovascular dysfunction and hard end points is warranted.