Compendium on the Pathophysiology and Treatment of Hypertension Preeclampsia Pathophysiology, Challenges, and Perspectives Sarosh Rana, Elizabeth Lemoine, Joey P. Granger, S. Ananth Karumanchi Abstract: Hypertensive disorders of pregnancy—chronic hypertension, gestational hypertension, and preeclampsia— are uniquely challenging as the pathology and its therapeutic management simultaneously affect mother and fetus, sometimes putting their well-being at odds with each other. Preeclampsia, in particular, is one of the most feared complications of pregnancy. Often presenting as new-onset hypertension and proteinuria during the third trimester, preeclampsia can progress rapidly to serious complications, including death of both mother and fetus. While the cause of preeclampsia is still debated, clinical and pathological studies suggest that the placenta is central to the pathogenesis of this syndrome. In this review, we will discuss the current evidence for the role of abnormal placentation and the role of placental factors such as the antiangiogenic factor, sFLT1 (soluble fms-like tyrosine kinase 1) in the pathogenesis of the maternal syndrome of preeclampsia. We will discuss angiogenic biomarker assays for disease-risk stratification and for the development of therapeutic strategies targeting the angiogenic pathway. Finally, we will review the substantial long-term cardiovascular and metabolic risks to mothers and children associated with gestational hypertensive disorders, in particular, preterm preeclampsia, and the need for an increased focus on interventional studies during the asymptomatic phase to delay the onset of cardiovascular disease in women. (Circ Res. 2019;124:1094-1112. DOI: 10.1161/CIRCRESAHA.118.313276.) Key Words: biomarkers ◼ blood pressure ◼ cardiovascular disease ◼ preeclampsia ◼ pregnancy Downloaded from http://ahajournals.org by on February 7, 2021 H ypertensive disorders are a common complication of pregnancy that put women and their fetuses at disproportionate risk for further complications, as well as life-long sequelae. Ranging in severity, hypertensive disorders of pregnancy include chronic hypertension—systolic blood pressure (BP) ≥140 mm Hg or diastolic BP ≥90 mm Hg that predates the onset of pregnancy; gestational hypertension—hypertension diagnosed after 20 weeks gestation without concurrent proteinuria; preeclampsia-eclampsia—classically, new-onset hypertension with new-onset proteinuria; and chronic hypertension with superimposed preeclampsia—chronic hypertension with new-onset proteinuria or other signs/symptoms of preeclampsia after 20 weeks or chronic proteinuria with newonset hypertension.1 With the greatest morbidity and mortality, preeclampsia affects 5% to 7% of all pregnant women but is responsible for over 70 000 maternal deaths and 500 000 fetal deaths worldwide every year. In the United States, it is a leading cause of maternal death, severe maternal morbidity, maternal intensive care admissions, cesarean section, and prematurity.2–4 Delivery can resolve most signs and symptoms; however, preeclampsia can persist after delivery and, in some cases, can develop de novo in the postpartum period.1,5 De novo or persistent postpartum preeclampsia has emerged as an important risk factor for peripartum morbidity in the United States.6 Hypertensive disorders of pregnancy and in particular preterm preeclampsia is also associated with substantial risk for cardiovascular disease (CVD) and cerebrovascular disease in the long-term.7,8 Epidemiology and Clinical Definition of Preeclampsia Risk Factors for Preeclampsia Risk factors for the development of preeclampsia have been studied extensively (Table 1). Major risk factors include a history of preeclampsia, chronic hypertension, pregestational diabetes mellitus, antiphospholipid syndrome, and obesity, among others.9 Other risk factors include advanced maternal age, nulliparity, history of chronic kidney disease, and use of assisted reproductive technologies. Relatively rare risk factors are a family history of preeclampsia and mother carrying a trisomy 13 fetus.10,11 Genetic susceptibility to preeclampsia has been extensively studied.12,13 A 2017 genome-wide association study analysis of neonates from 4380 cases of preeclampsia and 310 238 controls found a genome-wide susceptibility locus (rs4769613; P=5.4×10−11) near the FLT1 (FMS-like tyrosine kinase 1) gene, the protein From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Chicago, IL (S.R.); Harvard Medical School, Boston, MA (E.L.); Department of Physiology, University of Mississippi Medical Center, Jackson (J.P.G.); Departments of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (S.A.K.); and Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA (E.L., S.A.K.). Correspondence to S. Ananth Karumanchi, MD, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90004. Email sananth. [email protected] © 2019 American Heart Association, Inc. Circulation Research is available at https://www.ahajournals.org/journal/res 1094 DOI: 10.1161/CIRCRESAHA.118.313276 Rana et al Preeclampsia and Vascular Disease 1095 Nonstandard Abbreviations and Acronyms ACOG Arrb1 ASPRE Downloaded from http://ahajournals.org by on February 7, 2021 American College of Obstetrics and Gynecology β-arrestin-1 aspirin for evidence-based preeclampsia prevention trial AT1-AA Angiotensin II type 1 receptor autoantibodies AT1-B2 Angiotensin II type 1 receptor and Bradykinin B2 receptor complex BP blood pressure COMT catechol-O-methyl transferase CVD cardiovascular disease DV decidual vasculopathy ER endoplasmic reticulum ET-1 endothelin-1 FLT1 fms-like tyrosine kinase HELLP syndrome Hemolysis Elevated Liver enzymes Low Platelets syndrome HIF hypoxia-inducible factors HO heme oxygenase hsFLT1 human soluble FMS-like tyrosine kinase 1 KIR killer cell Ig-like receptors IL interleukin MHC major histocompatibility complex PAPP-A pregnancy-associated plasma protein A PGC-1a proangiogenic transcriptional cofactor- 1alpha PlGF placental growth factor PPCM peripartum cardiomyopathy PPV positive predictive value RNAi RNA interference technology ROS reactive oxygen species RR relative risk RUPP reduction in uterine perfusion pressure rodent model sENG soluble endoglin sFLT1 soluble fms-like tyrosine kinase 1 SGA small for gestational age StAmP Statins to ameliorate early onset preeclampsia trial STRIDER Sildenafil for severe fetal growth restriction trial TF transcription factor TGF-β1 transforming growth factor β1 Th1/Th2 T helper type 1/type 2 cells TNF Tumor necrosis factor uNK uterine natural killer cell UPR unfolded protein response VEGF vascular endothelial growth factor Table 1. Risk Factors for Preeclampsia Major Risk Factors Prior preeclampsia (RR, 8.4; 95% CI, 7.1–9.9) Chronic hypertension (RR, 5.1; 95% CI, 4.0–6.5) Pregestational diabetes mellitus (RR, 3.7; 95% CI, 3.1–4.3) Multiple gestation (RR, 2.9; 95% CI, 2.6–3.1) Prepregnancy BMI >30 (RR, 2.8; 95% CI, 2.6–3.1) Antiphospholipid syndrome (RR, 2.8; 95% CI, 1.8–4.3) Other risk factors Systemic lupus erythematosus (RR, 2.5; 95% CI, 1.0–6.3) History of stillbirth (RR, 2.4; 95% CI, 1.7–3.4) Prepregnancy BMI >25 (RR, 2.1; 95% CI, 2.0–2.2) Nulliparity (RR, 2.1; 95% CI, 1.9–2.4) Prior placental abruption (RR, 2.0; 95% CI, 1.4–2.7) Assisted reproductive technology (RR, 1.8; 95% CI, 1.6–2.1) Chronic kidney disease (RR, 1.8; 95% CI, 1.5–2.1) Advanced maternal age >35 (RR, 1.2; 95% CI, 1.1–1.3) Genetic susceptibility (mother, father) Rare risk factors Family history of preeclampsia Trisomy 13 fetus Relative Risk provided from meta-analyses by Ray et al.9 BMI indicates body mass index; and RR, relative risk. Clinical Definition of Preeclampsia Classically, the American College of Obstetrics and Gynecology (ACOG) defines preeclampsia as the presence of hypertension and proteinuria occurring after 20 weeks of gestation in a previously normotensive patient. However, a significant proportion of women develop systemic manifestations of preeclampsia—such as low platelets or elevated liver enzymes—before the hallmark of proteinuria is detectable,16,17 resulting in delayed diagnoses. The evolving understanding of preeclampsia as a heterogeneous hypertensive disorder of pregnancy led to ACOG’s hypertension 2013 task force to revise the definition of preeclampsia to include the presence of severe features with or without proteinuria and to exclude degree of proteinuria as a criterion of severe features (Table 2).1 These criteria were confirmed more recently in an update of the ACOG’s practice guidelines.18 Pathogenesis of Preeclampsia product of which is a well-established pathogenetic factor in preeclampsia.14 rs4769613 has a higher frequency in late-onset preeclampsia, exerts effects only in the fetal—not maternal—genome, and has no difference in transmission of disease association with parental sex inheritance, making the effects of imprinting unlikely. However, maternal genetic susceptibility may play a role as well. A multiethnic maternal preeclampsia genome-wide association study discovered a genome-wide susceptibility locus at rs9478812 (P=5.90×10−7), an intronic region of protein PLEKHGI implicated in BP regulation.15 A placental disease, preeclampsia progresses in 2 stages: (1) abnormal placentation early in the first trimester followed by (2) a “maternal syndrome in the later second and third trimesters characterized by an excess of antiangiogenic factors19,20 (Figure 1). While the mechanism of abnormal placentation is controversial, animal models have demonstrated that uteroplacental ischemia drives the hypertensive, multi-organ failure response observed in the maternal preeclamptic syndrome21 (stage 2). A number of theories have been proposed for the placental dysfunction observed in stage 1, including oxidative stress, abnormal natural killer cells (NKs) at the maternal-fetal interface, and genetic and 1096 Circulation Research March 29, 2019 Table 2. Clinical Definition of Preeclampsia1 Preeclampsia Elevated blood pressure Systolic ≥140 mm Hg or diastolic ≥90 mm Hg, 2 occasions, 4 h apart in previously normotensive woman AND Proteinuria ≥300 mg/24 hour urine collection or protein/creatinine ≥0.3 or dipstick reading =1+ OR severe features* Severe features Systolic blood pressure ≥160 mm Hg or diastolic ≥110 mm Hg, 2 occasions, 4 h apart on bedrest Thrombocytopenia (<100 000 μL) Liver function tests 2× normal or severe persistent right upper quadrant or epigastric pain Serum creatinine concentration >1.1 mg/dL or doubling of creatinine in the absence of other renal disease Pulmonary edema New-onset cerebral or visual symptoms Downloaded from http://ahajournals.org by on February 7, 2021 environmental factors, though none have conclusive evidence in humans. However, substantive evidence supports the idea that the diseased placenta leads to release of soluble toxic factors in the maternal circulation that result in inflammation, endothelial dysfunction, and maternal systemic disease.19,20,22 Stage 1: Abnormal Placentation, Trophoblast Invasion, and the Maternal-Fetal Interface During normal placental implantation, cytotrophoblasts migrate into the maternal uterine spiral arteries, forming vascular sinuses at the fetal-maternal interface to provide nutrition to the fetus. In normal pregnancy, this invasion progresses deeply into the spiral artery to the level of the myometrium,23,24 which leads to extensive remodeling of the maternal spiral arterioles into high capacitance, high flow vessels.23 In placentas destined to develop preeclampsia, cytotrophoblasts fail to transform from the proliferative epithelial subtype to the invasive endothelial subtype which causes incomplete remodeling of the spiral artery.25 Inadequate spiral arteriolar remodeling leads to narrow maternal vessels, and relative placental ischemia.26 The narrow spiral arteries are prone to atherosis—characterized by the presence of lipid-laden macrophages within the lumen, fibrinoid necrosis of the arterial wall, and a mononuclear perivascular infiltrate,27 leading to further compromise in placental flow. In humans, placental ischemia can be noninvasively identified using uterine artery Doppler studies. During normal pregnancy, uterine artery Doppler studies have confirmed robust systolic and diastolic uterine arterial flows; in contrast, women with preeclampsia have significant impairment of diastolic flow with a characteristic notch in the waveform that antedates clinical signs and symptoms of preeclampsia.28,29 These findings suggest that an abnormality in the trophoblasts themselves may result in shallow placentation and inadequate transformation of the spiral arteries, leading to placental ischemia and the maternal syndrome of preeclampsia.25 Atherosclerotic changes in maternal radial arteries that supply the decidua—as opposed to the spiral arteries—are also observed in preeclampsia.30,31 Decidual vasculopathy (DV) is a lesion common to disorders of placental insufficiency, including intrauterine growth restriction and preeclampsia, and combines (1) acute atherotic lesions with (2) medial hypertrophy and perivascular lymphocytes (Figure 2). Within preeclampsia phenotypes, the presence of DV is associated with worse clinical outcome, higher diastolic BP, worse renal function, and perinatal fetal death.32 Histologically, normal third-trimester decidual vessels are characterized by flat endothelium and a loss of medial smooth muscle, while preeclamptic decidua show signs of loose, edematous endothelium, hypertrophy of the vessel media, and loss of smooth muscle modifications (as seen in atherosclerosis), characterizing DV.30 Correlated with clinical diagnosis, DV has the highest association with preeclampsia with small for gestational age (SGA) and a lesser but significant association with SGA with doppler abnormalities, suggesting a pathogenetic similarity between SGA with doppler abnormalities and preeclampsia with SGA at the level of the decidua.30 Overall, there is significant evidence that decidual vessels demonstrate secondary atherosclerotic changes in preeclampsia. Further studies are needed to determine if these changes are representative of the maternal systemic endothelial damage secondary to pathological changes such as hypertension or if DV contributes to the pathogenesis of stage 1.30 In addition to uteroplacental insufficiency, epidemiological studies suggest that poor uterine decidualization—the stromal transformation of uterine endometrium to prepare for implantation—may affect the development of preeclampsia. Global transcriptional profiling of chorionic villus samples points to insufficient or defective decidualization in pregnancies that were later complicated by severe preeclampsia.33 Endometrial stromal cells from nonpregnant donors with a history of severe preeclampsia fail to decidualize in vitro and are transcriptionally inert, suggesting baseline genetic abnormalities or genetic modifications.34 Finally, global transcriptional profiling of decidual tissue from the women with preeclampsia also revealed defects in gene expression. These cells failed to redecidualize in culture, and their conditioned medium failed to support cytotrophoblast invasion, suggesting that decidual cells may be an important contributor to downregulated cytotrophoblast invasion in preeclampsia.34 The in vitro studies are confirmed ex vivo in histological studies of preeclampsia showing shallow placentation.31 Given the mounting evidence of fetal and maternal abnormalities in preeclampsia, defective placentation might be the result of combinations of factors that affect both trophoblast and decidua.35,36 Hypoxia and Trophoblast Invasion Upregulation of hypoxia-inducible transcription factors (TFs) and hypoxia-related gene signatures in the placenta suggest that hypoxia is central to the pathogenesis of preeclampsia.37 In the early phases of implantation, the gestational sac exists in a low oxygen tension environment, favoring trophoblast proliferation. Before the invasion, the proliferating trophoblasts anchor the blastocyst to maternal tissues and plug the tips of the spiral arteries within the decidua.38 Eventually these Rana et al Preeclampsia and Vascular Disease 1097 Figure 1. Schematic of the pathogenesis of preeclampsia. Genetic factors, immunologic factors, other maternal factors cause placental dysfunction which in turn leads to the release of antiangiogenic factors (such as sFLT1 [soluble fms-like tyrosine kinase 1] and sENG [soluble endoglin]) and other inflammatory mediators to induce preeclampsia. Downloaded from http://ahajournals.org by on February 7, 2021 trophoblastic-spiral artery plugs collapse, forming an intervillous space. The newly formed sinuses allow for the arrival of maternal blood, increasing oxygen tension, generating oxidative stress, and promoting trophoblast differentiation from a proliferative to an invasive phenotype that will invade and remodel the spiral arteries.39 HIF (Hypoxia-inducible factors)1α and -2α, markers of cellular oxygen deprivation, are expressed at high levels in proliferative trophoblasts and in the placentas of women with preeclampsia.40 Overexpression of HIF-1α in pregnant mice is associated with hypertension, proteinuria, and fetal growth restriction in mice41 and may result in failure of trophoblastic differentiation from the proliferative to the invasive phenotype.42 Furthermore, inhibition of HIF-1α by 2-methoxyestradiol, a metabolite of estradiol that destabilizes HIF-1α, suppresses the production of sFLT1 (soluble fms-like tyrosine kinase 1), a potent antiangiogenic factor known to contribute to the maternal syndrome.43 HIF1α expression is regulated by many factors in addition to hypoxia, therefore, isolating the dysregulated signal upstream is challenging.23,44 Magnetic resonance imaging has been used to assess the placental perfusion fraction—an estimate of the fraction of perfused tissue by volume—as a marker of uterine flow or placental function.45–47 In a Swedish study of 35 women with singleton pregnancies (13 with preeclampsia), Sohlberg et al47 found a smaller placental perfusion fraction associated with fetal growth restriction, as well as abnormalities in maternal and fetal vessel doppler flow, neonatal weight, and plasma markers, including higher levels of sFLT1. Novel blood oxygen level-dependent magnetic resonance imaging responses promise new, noninvasive, in vivo techniques for assessing maternal-fetal interface oxygen tension48,49 and may be useful for mapping areas of placental pathology and insufficiency.50 Oxidative Stress While low oxygen tension followed by maternal blood flow oxygenation results in normal placentation, intermittent hypoxia and reoxygenation caused by poor spiral artery invasion may cause oxidative stress. At the molecular level, preeclamptic placentas show an imbalance of reactive oxygen species Figure 2. Decidual vasculopathy. Placental bed of the uterus with decidual vasculopathy in the third trimester. Vessels show chronic injury with endothelial fragmentation and detachment (arrow) and fibrinoid necrosis (**) of the vessel wall. Scale bar is 100 μm. Reprinted from Hecht et al30 with permission. Copyright ©2016, Elsevier. 1098 Circulation Research March 29, 2019 Downloaded from http://ahajournals.org by on February 7, 2021 (ROS)-generating enzymes and antioxidants. In the ex vivo preeclamptic trophoblast, ROS-producing enzyme expression and activity are increased51 and inhibit the Wnt/β-catenin signaling pathway that promotes trophoblast invasiveness.52 Oxidative stress may also promote the transcription of antiangiogenic factors such as sFLT1.53 In humans, placental antioxidant mechanisms are impaired in patients with preeclampsia, as shown by their decreased expression of superoxide dismutase and glutathione peroxidase compared with women with normal pregnancies.54 However, treatment with the antioxidants Vitamin E and Vitamin C did not alter disease in women with preeclampsia, suggesting that ROS may be less integral to the pathway of the human syndrome.55,56 ROS may derive from mitochondrial stress. Zsengellér et al57 demonstrated decreased activity of the mitochondrial electron transport chain (ETC) enzyme cytochrome C oxidase in the syncytiotrophoblast cells of preeclamptic placentas, which correlated with increased placental sFLT1 expression. Based on evidence that hydrogen sulfide donors inhibit HIF-1α,58 Covarrubias et al59 demonstrated that AP39, a mitochondrialtargeting hydrogen sulfide donor, pretreatment could decrease sFLT1 expression in human syncytiotrophoblasts and increase cytochrome C oxidase activity in a dose-dependent fashion in normal and preeclamptic placentas, preventing the release of ROS and the subsequent stabilization of HIF-1α.60 Recently published studies with mitochondrial antioxidants in animal models of preeclampsia have also been promising.61 Another possible source of oxidative stress is endoplasmic reticulum stress caused by ischemia-reperfusion injury.62,63 Endoplasmic reticulum stress has been observed in the decidua and placentas of patients with fetal growth restriction and preeclampsia and triggers decidual cell and cytotrophoblast apoptosis through the activation of the UPR (unfolded protein response).64,65 PERK (PKR-like endoplasmic reticulm kinase), a transmembrane kinase that decreases the translational burden of the endoplasmic reticulum and upregulates proapoptotic TFs, has emerged as the leading signaling pathway implicated in preeclampsia.64,65 Interestingly, a recent study suggests that synergy between ATF4 (activating transcription factor 4), a TF downstream of PERK, and ATF6, a TF regulator of misfolded proteins in endoplasmic reticulum homeostasis,65,66 negatively regulate the transcription of PlGF (placental growth factor), an proangiogenic factor central to the pathogenesis of preeclampsia.67 Heme Oxygenase and Other Enzyme Abnormalities There is growing evidence that heme oxygenase (HO), the heme degradation catalyst, has an important role in the vascular function of the mother and the fetus, as well as in placental development and function.68–70 Three isoforms of HO have been characterized,68,71 with HO-2 playing a role in spiral artery invasion72 and HO-1 highly expressed in noninvasive trophoblastic phenotypes.73 Treatment of the reduced uterine perfusion pressure (RUPP) rodent model with CoPP (cobalt protoporphyrin), an inducer of HO-1, decreased BP and resulted in a proangiogenic shift in the VEGF (vascular endothelial growth factor)/sFLT1 ratio in the placenta.74 These preclinical studies have fueled interest in manipulating the expression of HO-1 as a potential therapeutic intervention for preeclampsia. Another influence on trophoblastic invasion and spiral artery remodeling may come from corin, a transmembrane enzyme that locally activates atrial natriuretic peptide through zymogen modification. Corin acts primarily in heart tissue, however, Cui et al75 found significantly decreased uterine-localized corin mRNA and protein levels as well as several corin gene mutations in preeclamptic patients. The group then created a knockout corin rodent model as well as transgenic crosses that retained isolated cardiac corin activity. Both phenotypes mimicked the hallmarks of preeclampsia, independently of preexisting hypertension or cardiac-derived atrial natriuretic peptide. However, in human studies, the evidence is mixed, as systemic levels of corin and its target—atrial natriuretic peptide—are upregulated during preeclampsia76,77 not downregulated as would be expected based on the animal studies. In earlier studies, women with hypertensive disorders of pregnancy were found to have lower levels of placental catechol-O-methyl transferase (COMT) enzyme,78 while women with normal gestations were found to have increasing concentrations of 2-methoxyestradiol, the COMT breakdown product of estradiol.79 Based on these observations, Kanasaki et al43 characterized a COMT knockout rodent model that reproduced the hallmarks of preeclampsia. However, COMT alterations are not a feature of severe early-onset preeclampsia in humans.80 Given that COMT is decreased in many hypertensive disorders of pregnancy,78 more evidence is required to implicate COMT in the pathogenesis of preeclampsia rather than a risk factor for all gestational hypertensive disorders. NK Cells and Impaired Placentation The uterine NK (uNK) is well characterized in decidualization physiology81 and may play a role in the abnormal placentation observed in preeclampsia. Unlike peripheral NKs, uNK is not cytotoxic.82,83 Rather, in the decidua, uNK cells regulate the depth of placentation, spiral artery remodeling, and trophoblastic invasion.84,85 As the main immunologic player interacting at the allogenic maternal-fetal cell interface,81 uNKs recognize self-major histocompatibility complexes (MHCs) derived from the maternal contribution and nonselfallogenic MHCs from the paternal genotype. Specifically, uNK express KIR (killer cell Ig-like receptors),86 while fetal invasive extravillous trophoblasts express the main KIR ligand, polymorphic HLA-C (human leukocyte antigen-C) MHCs.87 Because of independent segregation of maternal KIR and HLA loci86 and the paternal contribution to extravillous trophoblast HLA-C, every pregnancy results in a unique combination of KIR (maternal) and HLA-C (fetal) which may affect the success of placentation.83 Mouse models selected for nonmatched maternal uNK and paternal MHC molecules in otherwise genetically identical parents have demonstrated that allogenicity may promote decidual artery dilation, spiral artery remodeling, more efficient placentas, and larger fetal weights.88 In other words, inhibition of the uNK response by MHC-self recognition may lead to defective artery remodeling.89 Furthermore, certain maternal KIR haplotypes (uNK) appear protective against preeclampsia while others confer risk.83,90–92 However, the presence of the risk-associated haplotype is insufficient for disease, suggesting an additional environmental or genetic hit. Rana et al Preeclampsia and Vascular Disease 1099 Stage 2: Pathogenesis of the Maternal Syndrome Downloaded from http://ahajournals.org by on February 7, 2021 Imbalance in Circulating Angiogenic Factors More than a decade ago, several groups identified elevated levels of the antiangiogenic protein sFLT1 in placentas collected from women with a clinical diagnosis of preeclampsia.93,94 sFLT1 is a soluble protein that exerts antiangiogenic effects by binding to and inhibiting the biological activity of proangiogenic proteins VEGF and PlGF95 (Figure 3). VEGF is important for the maintenance of endothelial cell function, especially in fenestrated endothelium, which is found in the brain, liver, and glomeruli, the primary organs affected by preeclampsia.96 A member of the VEGF family, PlGF is important in angiogenesis and selectively binds to VEGFR1/sFLT1 not VEGFR2.97 Several findings implicated sFLT1 in the pathogenesis of preeclampsia: sFLT1 protein levels were high in maternal plasma or serum94,98; sFLT1 mRNA expression was high in preeclamptic placentas99; and injecting exogenous sFLT1 into rodents led to hypertension, proteinuria, glomerular endotheliosis (a hallmark of preeclampsia seen in renal biopsy), as well as several other preeclamptic features94,100; treatment of cancer patients with anti-VEGF drugs results in hypertension and proteinuria101,102; depletion of sFLT1 in preeclamptic plasma using antibodies reverses the antiangiogenic phenotype in cell culture studies93; lowering sFLT1 or antagonizing sFLT1 in animal models of preeclampsia improves clinical symptoms103–105 and, spontaneous resolution of clinical signs and symptoms of preeclampsia, when sFLT1 levels are lowered by 50% or more by treatment of the underlying placental conditions such as fetal hydrops or removal of diseased placenta in multiple pregnancies.106,107 In addition to the elevated sFLT1 levels, circulating levels of free PlGF were reduced in women with preeclampsia, suggesting an imbalance of antiangiogenic and proangiogenic proteins.94,108 The availability of robust immunoassays for angiogenic factors led to a number of clinical studies measuring the antiangiogenic/proangiogenic markers in large cohorts of human pregnancies showing that sFLT1 levels are high and free PlGF is low at the time of clinical diagnosis of preeclampsia as well as several weeks before the diagnosis.108,109 Angiogenic factor abnormalities in the plasma correlated with severity of presentation, predicting disease, and adverse outcomes.110,111 Early studies called into question the utility of angiogenic factors in prediction of preeclampsia.112 However, a recent multisite, blinded randomized trial for the use of aspirin for prevention of preeclampsia used several physiological and biochemical parameters, including PlGF, with a detection rate of 90% at a fixed false positive rate of 5% for preeclampsia, suggesting that the markers may be used algorithmically for early diagnosis.113 Such a strategy for prediction of the syndrome in early pregnancy would identify women who are at risk for developing the disease and who may benefit from preventative interventions such as aspirin. Early diagnosis would also reduce anxiety and unnecessary interventions in women at otherwise low risk of developing preeclampsia. Another antiangiogenic protein that has also been extensively studied in preeclampsia is soluble endoglin (sENG), an endogenous TGF-β1 (transforming growth factor β1) inhibitor114 (Figure 3). sENG is elevated in the sera of preeclamptic women 2 months before the onset of clinical signs of preeclampsia, correlates with disease severity, and falls after delivery.109,115 In pregnant rats, it appears to potentiate the vascular effects of sFLT1 to induce a severe preeclampsialike state, including the development of thrombocytopenia and fetal growth restriction,116,117 and, in combination with sFLT1, appears to induce cerebral edema resembling the reversible posterior leukoencephalopathy seen in patients with eclampsia.118,119 Inflammatory Cytokines and Immune Cell Alterations It is well-established that preeclampsia is a proinflammatory state, but the culpable cells have yet to be fully elucidated. Syncytial knots120,121 are allogenic nano to microvesicles shed from apoptotic or activated trophoblasts121 that have been identified in the lungs120,122 and plasma of normal pregnancies and in increased amounts in preeclampsia.122–124 Rich in sFLT1 and endoglin,125,126 syncytiotrophoblast microvesicles and exosomes may instigate an inflammatory response. In vitro, syncytiotrophoblast microvesicles activate cultured peripheral blood mononuclear cells, causing a release of proinflammatory cytokines124,127 that is even more robust when exposed to peripheral blood mononuclear cells from pregnant patients.127 However, in vitro data are not consistent, as microvesicles induced by an alternative mechanism are not proinflammatory.128,129 IL (Interleukin)-10—a cytokine that induces the differentiation of the T cell into the Th (T helper type)2 phenotype— stands out in the literature as an important mitigator of the maternal syndrome by neutralizing proinflammatory cytokines, AT1-AA (angiotensin II receptor 1 autoantibodies), placental ROS, and ET-1 (endothelin-1).130 Many cell types in preeclamptic patients demonstrate a dysregulation in the balance of IL-10 and proinflammatory cytokines,131–133 including uterine and circulating NKs134 and peripheral blood mononuclear cells. Studies of peripheral blood mononuclear cells of preeclamptic women had reduced IL-10 secretion,135–138 which may lead to failure of T-cell differentiation. Commonly referred to as Th2 polarization, normal pregnancy is characterized by a shift in T-cell phenotype towards Th2 relative to Th1.139,140 Multiple studies have reported an aberrant shift towards the Th1 phenotype in preeclampsia, resulting in insufficient trophoblast invasion.141 Furthermore, a preeclamptic-like syndrome can be induced in normal pregnant rats with transfer of CD4+ cells obtained from RUPP models.122 Preeclampsia is also associated with elevated complement levels142,143 and with genetic mutations in C3.144 In animal models, complement inhibition restores spiral artery capacitance145 and decreases sFLT1 production,146 and a C1q knockout mouse model mimics preeclamptic features.147,148 However, complement dysregulation is most severe in the form of severe preeclampsia called hemolysis elevated liver enzymes low platelets (HELLP) syndrome. HELLP syndrome has been shown to share a genetic mutation with149 and has a similar presentation to atypical hemolytic uremic syndrome, a disease thought to be caused by uncontrolled complement activation.150–152 Interestingly, many of the same complement pathway mutations found in hemolytic uremic syndrome are also associated with preeclampsia.142,150 Further evidence to 1100 Circulation Research March 29, 2019 Figure 3. sFLT1 (soluble fms-like tyrosine kinase 1) and sENG (soluble endoglin) causes endothelial dysfunction by antagonizing VEGF (vascular endothelial growth factor) and TGF (transforming growth factor)-β1 signaling. There is mounting evidence that VEGF and TGF-β1 are required to maintain endothelial health in several tissues including the kidney and perhaps the placenta. During normal pregnancy, vascular homeostasis is maintained by physiological levels of VEGF and TGF-β1 signaling in the vasculature. In preeclampsia, excess placental secretion of sFLT1 and sENG (2 endogenous circulating antiangiogenic proteins) inhibits VEGF and TGF-β1 signaling respectively in the vasculature. This results in endothelial cell dysfunction, including decreased prostacyclin, nitric oxide production, and release of procoagulant proteins. Reprinted from Powe et al114 with permission. Copyright ©2011, the American Heart Association. Downloaded from http://ahajournals.org by on February 7, 2021 the pathogenic link between atypical hemolytic uremic syndrome and HELLP, a patient presenting with early-onset severe preeclampsia and HELLP was able to delay delivery by 17 days after treatment with Eculizumab,153 an Food and Drug Administration-approved C5 inhibitor used to treat atypical hemolytic uremic syndrome 154,155 including in pregnancy.156 The use of Eculizumab as an effective treatment for a severe form of preeclampsia is promising, however, HELLP is diagnostically difficult to distinguish from atypical hemolytic uremic syndrome,157 likely because of the overlap in complement pathology. Renin-Angiotensin Pathway There is evidence for alterations in the renin-angiotensinaldosterone system in the pathogenesis of preeclampsia.158 Several studies show enhanced angiotensin II sensitivity during and before the onset of preeclampsia despite reduced circulating renin and angiotensin II during preeclampsia when compared with normal pregnancy.159,160 One potential mechanism for the increased angiotensin II sensitivity is the presence of circulating autoantibodies to AT1 in the sera of preeclamptic women.161,162 In preclinical studies, autoantibodies to AT1 reproduce many of the hallmark characteristics of preeclampsia: vasoconstriction through activation of ET-1163; endothelial cell necrosis and apoptosis in human umbilical vein endothelial cells164; stimulation of tissue factor production contributing to hypercoagulation165; reduction of trophoblast invasion in human cell culture models166; and increased production of ROS in culture models.167 Produced in response to placental ischemia and systemic inflammation,168 anti-AT1-AA can also stimulate placental production of antiangiogenic factors sFLT1 and sENG.169 Finally, CD19+CD5+ cells, as well as anti-AT1-AA activity, are elevated in the sera of preeclamptic patients, implicating B lymphocytes as an immune player.170 These findings suggest that anti-AT1-AA made by a subpopulation of CD19+CD5+ in response to placental ischemia and systemic inflammation may contribute to the hypertension and production of antiangiogenic factors that characterize the maternal syndrome. Recent preclinical studies on the hypersensitivity of the AT1 receptor when complexed with the bradykinin B2 receptor provide compelling evidence for another model for the activation of the renin-angiotensin-aldosterone system in the setting of downregulated renin.171 Using a new transgenic mouse model with maternal, systemically upregulated smooth muscle AT1-B2 complexes, the group was able to replicate the preeclampsia syndrome, with pregnant animals developing hypertension, proteinuria, low platelets, increased sFLT1, AT1-AA, and ET-1, smaller litter sizes, intrauterine growth restriction, lower renin levels, and a decreased placental labyrinth layer. Furthermore, when heteromerized with B2, ATI seems independently sensitive to angiotensin II and mechanostimulation, which, the authors suggest, may evolve with an increase in fetal-placental mass regardless of renin activity. The preeclamptic-like transgenic mice were then rescued with lentiviral administration of an inactivation-resistant variant of Arrb1 (β-arrestin-1), G-protein coupled receptor-associated protein that desensitizes the AT1 receptor leading to signal dampening. In ex vivo studies of human placentas, the group found significantly elevated levels of inactivated (phosphorylated) levels of Arrb1 in preeclamptic placentas compared with normotensive placentas, as well as increased AT1-B2 complex formation on the vessels of the basal plate of a preeclamptic placenta. Though the AT1-B2 model does appear to replicate the maternal syndrome well, only a small number of human placentas were analyzed as part of this study. Rana et al Preeclampsia and Vascular Disease 1101 Additional human studies are required to assess applicability of this model to the biology of preeclampsia. Elevated levels of an oxidized form of angiotensinogen that is more readily cleaved by renin have also been implicated in the pathogenesis of the hypertension observed in preeclampsia.172 However, robust assays to measure this modified form of angiotensinogen in the blood are needed to characterize a role for oxidized angiotensinogen in preeclampsia. Finally, in animal models, elevated levels of circulating sFLT1 were sufficient to induce angiotensin II sensitivity by interfering with endothelial nitric oxide production.173 Downloaded from http://ahajournals.org by on February 7, 2021 Sympathetic Nervous System While a major emphasis of study in the pathogenesis of preeclampsia has been on the link between placental factors and maternal endothelial dysfunction, several studies have implicated the sympathetic nervous system in the pathogenesis of preeclampsia.174,175 Schobel et al174 observed that muscle sympathetic nerve activity is elevated in women with preeclampsia over normal pregnant and hypertensive, nonpregnant control women. Women with preeclampsia also have reduced baroreflex sensitivity and greater antihypertensive responses to nonselective adrenergic receptor blockade.176,177 Studies using experimental animal models supports that sympathetic nerve activity is increased in preeclampsia. Placental ischemia-induced hypertension in the RUPP rat model is associated with a hypertensive shift in baroreceptor control on renal sympathetic nerve activity, 178 and a recent study found that adrenergic receptor blockade markedly attenuates placental ischemia-induced hypertension.179 Collectively, studies from humans and animal models suggest that an intact sympathetic nervous system may be important in eliciting the full hypertensive response to factors released in response to placental ischemia. Lessons From Animal Models One of the many challenges of the study of preeclampsia is its reproducibility in animal models. Spontaneous preeclampsia is unique to human gestation. Therefore, animal models approximate rather than replicate the disease, predominantly through evidence of systolic hypertension, renal endotheliosis, proteinuria, and, at times, fetal growth restriction and production of antiangiogenic factors.180 The RUPP rodent model, produced by clipping the abdominal aorta and the main uterine arteries of pregnant Sprague-Dawley rats,181 is most commonly used and presents with elevated mean arterial pressure, greater vascular reactivity to α-adrenergic agonists181 and increased production of AT1-AA, ROS, and sFLT1 and sENG as observed in preeclamptic women.182 Other animals, including pregnant rabbits, rhesus monkeys, and baboons, have also been used to model preeclampsia by inducing uteroplacental insufficiency.182 To replicate the placenta as the inherently pathogenic organ rather than as secondary to uterine ischemia, Kumasawa et al104 implanted mice with transgenic blastocysts with trophectodermal layers expressing human sFLT1 via lentiviral vectors. Human sFLT1 levels increased in the maternal serum as gestation progressed, with corresponding development of the hallmarks of preeclampsia. However, the rodents did not develop the full spectrum of severe features as in humans. Genetic rodent models, such as the BPH/5 model, have been used as well. Mildly hypertensive at baseline, the BPH/5 model demonstrates elevated mean arterial pressure, proteinuria, and progressive glomerular damage in late gestation and delivers significantly smaller litters than controls.183 The previously discussed COMT knockout rodent model similarly presents with systolic hypertension, elevated sFLT1, and proteinuria that decline after parturition, however, there is no evidence of systemic vascular damage or fetal growth restriction, suggesting that this model approximates gestational hypertension or mild preeclampsia.43 The C1q knockout mouse model relies on the observation of the complement factor C1q at the decidual endothelium-trophoblast interface184 and was found to have small litters, intrauterine growth restriction, elevated BP, proteinuria, elevated levels of sFLT1, and evidence of endothelial dysfunction.147,148 Systemic delivery of arginine vasopressin was also sufficient to induce preeclampsialike state in pregnant mice, but lack of placental hypoxia and sFLT1 upregulation in this model suggest that it may be more relevant for term preeclampsia that is often characterized by modest levels of antiangiogenic biomarkers.185 Older rodent models manipulate the renin-angiotensin system (placental renin and maternal angiotensinogen) to model pregnancy-induced hypertension,186 however, the relevance of this model to human disease is questionable as humans with preeclampsia are characterized by suppressed renin and angiotensin II when compared with normal pregnancy. Primarily designed on the observation that placental ischemia induces systemic hypertension, the described animal models have been useful for characterizing the molecular environment of uteroplacental hypoperfusion as well as a variety of cytokines and proteins released into the maternal circulation. Animal models can be used to extend correlation data observed in humans into cause and effect relationships, as has been seen in sFLT1 and sENG manipulation in RUPP models, and are critical tools for assessing toxicity and efficacy in novel therapeutics. Of course, animal models are imperfect for this human-specific disease, as they fail to demonstrate thrombocytopenia, HELLP syndrome, eclamptic seizures, and other signs and symptoms that define the severe features of preeclampsia in humans. Perhaps, the imperfect overlap in presentation stems from the fact that the primary driver of preeclampsia, insufficient trophoblast invasion and failure of spiral artery remodeling, does not occur naturally in other species and has yet to be modeled accurately. In fact, rodent trophoblasts minimally invade the spiral arteries, as decidualization occurs after implantation,187 and therefore, may be an inherently insufficient model species. Furthermore, human gestation is significantly longer than in rodents, and exposes pregnant women to much larger doses of circulating toxins, such as sFLT1, possibly leading to severe features. In fact, when sFLT1 and sENG levels are concurrently pushed to exaggerated levels, severe features do occur in animal models.108–110,113 Despite their limitations, experimental studies in animal models allow investigators to test directly whether certain factors found in women with preeclampsia can indeed lead to hypertension and other manifestations of the syndrome. Further investigation is necessary with models that better approximate human gestation physiology and length to isolate the primary pathogenic factors. 1102 Circulation Research March 29, 2019 Downloaded from http://ahajournals.org by on February 7, 2021 Maternal Contribution to Disease Epidemiological studies suggest that several prepregnancy maternal characteristics increase risk for preeclampsia.188 Interest is growing around obesity and diabetes mellitus as risk factors (relative risk [RR], ≈3.5 each)189 in light of data suggesting Metformin, the biguanide first-line therapy for type 2 diabetes mellitus, may decrease sFLT1.190 In a recent meta-analysis of 15 randomized controlled trials reporting the incidence of hypertensive disorders of pregnancy with Metformin use, Kalafat et al191 found a reduced risk of hypertensive disorders of pregnancy (RR, 0.56; 95% CI, 0.37–0.85) but a nonsignificantly reduced risk of preeclampsia (RR, 0.74; 95% CI, 0.09–6.28). However, authors admit the low quality of the evidence and the clinical heterogeneity of the included studies, limiting conclusions. Prepregnancy vascular dysfunction, such as in women with chronic hypertension, not only jeopardizes placental perfusion but may also enhance the placental response to ischemia as well as the vascular response to antiangiogenic factors such as sFLT1. Therefore, baseline host characteristics may put women at risk of preeclampsia, even at physiological elevations of antiangiogenic factors and cytokines. A history of acute kidney injury before pregnancy, despite apparent full recovery, is also associated with increased risk of pregnancy complications.192 Interestingly, a shorter interval between the AKI episode and the pregnancy were associated with higher risks of preeclampsia. This suggests that subclinical renal dysfunction may interfere with the hemodynamic adaptation of normal pregnancy, which in turn may lead to impaired placental perfusion and preeclampsia.192 Translation of Preeclampsia Biology in the Clinic Biomarkers for Diagnosis, Prediction, and Prognosis The ACOG committee opinion issued in 2015 and reaffirmed in 2017 does not recommend screening to predict preeclampsia beyond obtaining an appropriate medical history.18,193 Because of the lack of adequate screening methods and the severe sequelae of the disease, all women suspected of preeclampsia undergo resource intensive testing, often requiring several-day hospitalizations for further investigation. Other methods of screening have been investigated, including a metabolomic pathways and combined metabolomic-proteomic data approaches.194–197 A 2017 head to head comparison of the Fetal Medicine Foundation algorithm-based screening method (a combination of maternal factors, mean arterial pressure, uterine-artery pulsatility index, and PlGF) demonstrated superiority to the screening methods currently recommended by National Institute for Health and Care Excellence and ACOG.198 Using a similar screening algorithm with the addition of maternal serum PAPP-A (pregnancy-associated plasma protein-A), the ASPRE trial (aspirin for evidence-based preeclampsia prevention) screened women in the first trimester to identify those at high risk for preeclampsia.199 High-risk women were then randomized to receive 150 mg of aspirin or placebo daily until 36 weeks gestation. Daily low-dose aspirin use in high-risk women was associated with a significantly lower incidence of preterm preeclampsia than placebo, and detection rate of preterm preeclampsia was 76.7% (138/180)—43.1% for term preeclampsia—with a false positive rate of 9.1%. These results suggest that early screening with plasma biomarkers and imaging studies allows for early intervention and possible prevention of disease. Perhaps most promising among screening methods is the use during the third trimester of combined biomarkers—such as sFLT1, sEng, and PlGF—with high sensitivity and specificity for early diagnosis and prognosis of preeclampsia.200 Substantial evidence already demonstrates encouraging test characteristics of biomarker assays in this population.201,202 In a study of over 600 women undergoing initial evaluation of preeclampsia, an sFLT1/PlGF ratio of ≥85 correlated with diagnosis of preeclampsia and predicted adverse outcomes and delivery within 2 weeks among women presenting <34 weeks gestation. Furthermore, the biomarker ratio performed better than all other currently available tests for prediction of preeclampsia.110 A follow-up study of 402 patients presenting with preterm singleton pregnancies by the same group showed that an sFLT1/PlGF ratio >85 had a PPV of 59% in all patients and 74% among patients presenting <34 weeks for developing preeclampsia with severe features within 2 weeks.203 Patients with preeclampsia with normal angiogenic profile have fewer adverse outcomes suggesting that the angiogenic form of preeclampsia is clinically more important.111 Other groups have shown similar results. In a multicenter study of women with suspected preeclampsia, authors showed a reverse association of free PlGF with gestational age at delivery.204 In a recent multisite study of angiogenic factors, authors concluded that an sFLT1/PlGF ratio of ≤38 had an negative predictive value of 99.9% for ruling out preeclampsia within 1 week.205 A follow-up study from the same cohort showed an negative predictive value of 95% within 4 weeks.206 Overall, serum or plasma angiogenic factors appear to be a reliable risk-stratification method among women with suspected preeclampsia, especially for preterm preeclampsia, allowing for appropriate management. Recent studies have also suggested that by reducing false positive rates of diagnosis and consequent unnecessary hospitalizations, risk stratification with biomarkers is economical. Assays using these plasma biomarkers are available for clinical use in Europe, Canada, Africa, and Asia, and their clinical success has led to the incorporation of angiogenic factors in the definition of preeclampsia in the British National Institute for Health and Care Excellence and national German guidelines.207 Finally, a study in Mozambique showed that measurement of PlGF is feasible in resource poor environments. The authors concluded that low PlGF in women with suspected preeclampsia was associated with increased transfers to higher levels of care and increased maternal and perinatal risks.208 Looking forward, biomarker assays are a cost-effective and reliable screening method that could be lifesaving, even in areas of limited expertise and resources. Though not part of any formal diagnostic criteria, hyperuricemia is classically a biomarker indicating progression of gestational or chronic hypertension to preeclampsia and of risk for fetal and maternal complications such as SGA.209–212 However, in all-comers, uric acid levels do not predict development of preeclampsia.213–215 Evidence about the contribution of uric acid to the pathogenesis of preeclampsia is mixed, Rana et al Preeclampsia and Vascular Disease 1103 though general consensus suggests that levels are elevated secondary to renal injury and decreased excretion.216 Treatment and Management of Preeclampsia Downloaded from http://ahajournals.org by on February 7, 2021 Current management of preeclampsia in the developed world includes preconception counseling, perinatal BP control and monitoring, prenatal aspirin therapy in high-risk women, betamethasone for patients <34 weeks, parenteral magnesium sulfate, and careful follow-up of postpartum BPs.1 Timely delivery of the fetus and placenta remains the only definitive treatment. Even among patients who did not show antenatal signs of preeclampsia, surveillance continues postpartum because of the rising incidence of postpartum preeclampsia. Preeclampsia without severe features can be managed expectantly with twice-weekly maternal and fetal monitoring until 37 weeks in the absence of labor, rupture of membranes, vaginal bleeding, or abnormal antepartum testing.1,18 In women with preeclampsia with severe features at <34 weeks, expectant management can be attempted based on strict inclusion criteria and with appropriate resources. In these patients, careful attention should be given to worsening maternal and fetal well-being and delivery is indicated at any time with deterioration of maternal and fetal status. ACOG currently does not recommend pharmacological treatment of mild to moderate range hypertension (systolic <160 mm Hg or diastolic <110 mm Hg) in the setting of preeclampsia,1 as it does not appear to attenuate risk of disease progression and may increase the risk of fetal growth restriction.217 In a multinational randomized trial for control of BPs enrolling women with chronic and gestational hypertension, authors found lower prevalence of severe hypertension (≥160/110 mm Hg) among patients with tight control of BPs during pregnancy (40.6% versus 27.5%). There was no difference in development of preeclampsia and perinatal outcomes were similar.218 A large randomized trial is underway in the United States to evaluate treatment of moderate hypertension during pregnancy (URL: http://www.clinicaltrials.gov. Unique identifier: NCT02299414). Treatment of severe hypertension requires pharmacological therapy with labetalol, nifedipine, or methyldopa,1 however, recent evidence from animal studies suggest that amlodipine may be superior to nifedipine because of its inducing effects on Arrb1 and subsequent downregulation of the AT1-B2 receptor complex,171 though more clinical evidence is needed. Though current clinical management is limited, innovative medical therapies are on the horizon. Small molecules have had variable success in treating hypertensive disorders of pregnancy. Early studies, including the 1998 National Institutes of Health trial, did not show improved outcomes in women at high risk of preeclampsia when treated with low dose (60 mg) of aspirin compared with placebo.219 However, with improved risk-stratification methods, Rolnik et al199 demonstrated a lower incidence of preterm preeclampsia in high-risk women treated with 150 mg of aspiring compared with placebo. Aspirin is now recommended for the prevention of preeclampsia in high-risk women.1 Sildenafil, a phosphodiesterase type 5 inhibitor, was initially thought to be a promising way to reduce placental ischemia given its ability to potentiate the actions of nitric oxide, causing uterine vasodilation. However, in the 2018 Maternal STRIDER trial (Sildenafil for Severe Fetal Growth Restriction), sildenafil did not prolong pregnancy or improve pregnancy outcomes compared with placebo in women with severe intrauterine growth restriction in the late second to third trimester.220 A 2017 randomized controlled trial of sildenafil therapy in fetal growth restriction did not show any benefit in attenuating disease compared with placebo221 and was prematurely halted when 11 neonates in the sildenafil arm died secondary to pulmonary disease.222 However, other small molecules that effect nitric oxide production are still under investigation. For example, statins continue to show promise in animal models and in human ex vivo tissue samples.223–225 Likely because of its stimulatory effects on HO and improved vascular function,224 pravastatin improves fetal and maternal outcomes in patients with antiphospholipid syndrome226 and mitigates disease in patients with severe features225 and with evidence of placental vascular pathology.227 StAmP trial (Statins to Ameliorate Early Onset Preeclampsia), a double-blind, multicenter, randomized controlled trial looking at the effects of Pravastatin on serum biomarkers in preeclampsia, has completed recruitment and is now in the data-analysis phase (ISRCTN 23410175). Metformin, an insulin sensitizer and the first-line treatment of type 2 diabetes mellitus, is associated with reduced incidence of hypertensive disorders in pregnancy,191 as well as decreased levels of circulating sFLT1 and sENG in vitro.228 Metformin has been shown to be safe in pregnancy, with no significant difference in neonatal outcomes when compared with insulin in the treatment of gestational diabetes mellitus,229 making Metformin an attractive and readily available therapy. Finally, ouabain, a cardiac glycoside, has been shown to inhibit sFLT1 mRNA and protein expression through the HIF-1α/heat-shock protein 27 pathway in human cytotrophoblasts and explant cultures as well as in rat models without any fetal adverse effects.230 Further investigation is necessary to further characterize ouabain as a therapeutic. Most small molecules target the prevention of preeclampsia in high-risk women, however, no therapy currently exists for the treatment of preeclampsia to delay preterm delivery. Adapting apheresis technology safely and commonly used in pregnant women with familial hypercholesterolemia,231 Thadhani et al232 used a negatively charged dextran sulfate cellulose column to remove positively charged sFLT1 from the serum of 3 women with preterm (<32 weeks) preeclampsia, resulting in dose-dependent delays in delivery. To minimize the side effect profile—namely, transient hypotension—and improve the efficiency of removal, the same group repeated the pilot study with an apheresis device that incorporated plasma separation for sFLT1 removal.233 Eleven women with very preterm preeclampsia were treated with dextran sulfate column apheresis with a mean reduction in sFLT1 of 18% per treatment and an average of 8 days (range 2–11) of extended gestation with a single treatment and an average of 15 days (range 11–21) extended gestation with multiple treatments, compared with an average of 3 to 4 days in controls. There were no additional adverse events in neonates treated with apheresis compared with normal and preeclamptic controls born comparably preterm. Direct therapies for the treatment of preeclampsia would revolutionize the management of this highly morbid disease, and the results from these pilot studies 1104 Circulation Research March 29, 2019 show immense promise, with refinement of the specificity of the apheretic column for known preeclamptic markers. Other promising therapies for preeclampsia include recombinant human PlGF and RNA interference technology-based methods. A ligand specific to VEGFR1/Flt1, recombinant human PlGF has the potential to scavenge excess circulating sFLT1 without the additional side effects of vascular permeability and edema associated with VEGFR2. Baboon and rodent studies have shown promising results, lowering BP, proteinuria, and sFLT1 mRNA.234,235 However, the treatment may be limited given that only a small percentage of total body sFLT1 is circulating236 and, therefore, amenable to ligand interaction. RNA interference technology provides a cheaper alternative to recombinant therapies. Silencing sequences of RNA specific to all 3 isoforms of circulating sFLT1 mRNA have been shown to decrease sFLT1, BP, and proteinuria in pregnant baboon models with a single dose.237 However, given the limitations of animal models of preeclampsia and the regulatory implications of developing oligonucleotide therapies, significant further study is required before clinical trials. Preeclampsia and CVD Short-Term Cardiovascular Complications in the Postpartum Period Downloaded from http://ahajournals.org by on February 7, 2021 Postpartum hypertension (defined as hypertension >48 hours or more after delivery) occurring either de novo or in the setting of preeclampsia has emerged as an important risk factor for significant morbidity in women in the United States.238 While the pathogenesis of this syndrome is still being elucidated, clinical studies have suggested that postpartum hypertension may share similar plasma angiogenic profiles as women with antepartum preeclampsia and, therefore, may represent a group of women with subclinical preeclampsia or unresolved preeclampsia.5 In the peripartum period, preeclampsia is associated with an increased risk of peripartum cardiomyopathy (PPCM) that can progress to chronic heart failure, cardiac transplantation, or death.239,240 Given that VEGF pathway inhibitors in oncology patients also induce cardiomyopathy,241 elevated levels of antiangiogenic factors may play a role in the development of PPCM. Using a PGC (proangiogenic transcriptional cofactor)-1α knockout mouse model and human serum studies, Patten et al240 showed that repeatedly elevated levels of sFLT1 and prolactin cleavage fragments were synergistically associated with PPCM and that both angiogenic factor imbalance and prolactin fragmentation are regulated by PGC-1α. Authors proposed a 2-hit hypothesis for the development of PPCM: (1) an increase in antiangiogenic factors such as sFLT1 that causes cardiac dysfunction as seen in preeclampsia and (2) an independent decrease in defenses against antiangiogenic factors in the heart as seen in low levels of cardiac PGC-1α expression. Thus, inhibition or removal of sFLT1 could attenuate PPCM in preeclamptic women with an environmental or genetic predisposition to disease. In the short-term, neonates may also present with vascular effects secondary to the elevated levels of antiangiogenic factors. Though hypertension and proteinuria observed in the mother are not observed in the fetus, elevated levels of sFLT1 have been observed in the amniotic fluid in women with preeclampsia.242 Epidemiological studies have shown an increased incidence of bronchopulmonary dysplasia243,244 and decreased incidence of retinopathy of prematurity (adjusted odds ratio 0.65; 95% CI, 0.49–0.86 for early preterm),245 2 diseases of prematurity associated with neoangiogenesis. Intraamniotic injections of sFlt1 in rat models disrupt pulmonary angiogenesis and increase the incidence of bronchopulmonary dysplasia,244 while administration of anti-sFLT1 monoclonal antibody increases alveolar counts and pulmonary vessel density in the premature pups of preeclampsia rat models.246 Together, these epidemiological and animal studies imply that sFLT1 affects fetal angiogenesis at mucous membranes exposed to amniotic fluid. Preeclampsia and Long-Term CVD There is accumulating evidence that preeclampsia-eclampsia predisposes to long-term cardiovascular risk247,248 including risk of hypertension, peripheral arterial disease (RR, 1.87; 0.94–3.73), coronary artery disease (overall CVD RR: 2.3; 1.95–2.78), cerebrovascular disease (RR, 2.03; 1.54–2.67), congestive heart failure, vascular dementia (hazard ratio, 3.46; 1.97–6.10), and death (RR, 2.29; 1.73–3.04).248–250 Potential explanations for the association between preeclampsia and CVD are debated. It has been proposed that endothelial damage caused by preeclampsia persists beyond postpartum recovery, increasing the risk of CVD,247 and that the risk of future CVD increases with multiple episodes of preeclampsia.248 Alternatively, an unfavorable cardiovascular risk profile characterized by higher levels of glucose, cholesterol, hypertension, and abdominal obesity may contribute to the development of preeclampsia and later, CVD.249 The odds of a fatal outcome from CVD have been shown to be greater than odds of diagnosis (odds ratio =2.89; 95% CI, 1.71–4.89 and odds ratio =2.01; 95% CI, 1.68–2.41; respectively)250 in preeclampsia, suggesting that women may die from the sequelae of CVD without first being diagnosed. Furthermore, meta-regression reveals a graded relationship between the severity of preeclampsia-eclampsia and the risk of cardiac disease (mild: RR 2.00, 1.83–2.19; moderate: RR 2.99, 2.51–3.58; and severe: RR 5.36, 3.96–7.27; P<0.0001), implicating a dose-response to the severity of preeclampsia.249 Studies are underway to find biomarkers and subclinical echocardiographic measures, such as global longitudinal strain,251–253 to provide early risk assessment and stratification in women with preeclampsia. The question remains if there is an opportunity for intervention in asymptomatic women with a history of preeclampsia. A study of 2 tertiary medical centers in the Netherlands254 found that a total of 42% of women with a history of preeclampsia had significant CVD risk factors compared with 14.3% among women with a history of an uncomplicated pregnancy. In the United States, a 2018 study using the Nurses’ Health Study II suggested that hypertensive disorders of pregnancy were associated with 10-year CVD risk overall, independent of established CVD risk factors. Globally there is increasing evidence that a history of preeclampsia should be considered in CVD risk stratification.7 Rana et al Preeclampsia and Vascular Disease 1105 Preeclampsia is also associated with 4.7-fold risk for subsequent end-stage renal disease.255 Based on sibling studies, Vikse et al256 reported that familial aggregation of risk factors could not explain the increased end-stage renal disease risk and, therefore, concluded that preeclampsia per se may lead to long-term kidney damage. Women with preeclampsia are also at a 4-fold risk of stroke257 and 3-fold risk of vascular dementia later in life.258 Additional studies are needed to elucidate the pathogenesis of these long-term complications in women with preeclampsia. Decades of literature observe a relationship between lifelong CVD risk and growth restriction in utero, such as seen in the fetuses of preeclamptic pregnancies. First described by Barker and Osmond,259 the so-called Barker Hypothesis suggests that lack of early nutrition, growth restriction, and the uterine environment increase susceptibility to other risks for CVD. Indeed, children born to women with preeclampsia have an increased risk of CVD.260 Neonates may also be at risk for pulmonary hypertension into their teenage years and beyond.261 Pulmonary amniotic sFLT1 exposure leading to decreased pulmonary angiogenesis has been proposed as a mechanism for this long-term lung injury,246 though the sequelae of prematurity or systemic sFLT1 exposure246 cannot be excluded. Current research seeks to further characterize CVD in children born to preeclamptic mothers.262 Conclusions Downloaded from http://ahajournals.org by on February 7, 2021 Preeclampsia is a leading cause of maternal morbidity and mortality worldwide, whose only definitive treatment—delivery of the fetus and placenta—carries significant morbidity and mortality for the neonate. Though the mortality of preeclampsia-eclampsia has decreased significantly in the United States because of increased antenatal surveillance and early interventions, the postpartum and lifelong sequelae of preeclampsia have risen in number and significance. Whether the risk predates and confounds preeclampsia or is a result thereof, we now know that women with a history of preeclampsia are at increased risk for CVD250,263 and dementia258 later in life, including acutely fatal myocardial infarction without the progressive, forewarning symptoms of the acute coronary syndrome.263 An increased focus on interventional studies during the postpartum, asymptomatic phase is imperative to minimize the risk of CVD and its potentially fatal complications. Improved risk stratification and therapeutics are other areas of opportunity with several innovations on the horizon. While ongoing work in placental oxidative stress and the maternal immune response demonstrate intriguing insights, perhaps the most promising area under investigation is the maternal angiogenic factor imbalance and its effects on vascular function. Ongoing development of methods of risk stratification using ratios of proangiogenic factors—such as PlGF—and antiangiogenic factors—such as sFLT1 and sENG—have high detection rates for preterm preeclampsia when incorporated into algorithms with other predictive elements264 and have shown high negative predictive value as an isolated assay. Removal of antiangiogenic proteins through plasma apheresis significantly prolongs gestation compared with controls and attenuates the symptoms of preeclampsia,232,233 and recombinant human PlGF and siRNA have shown promising results in animal models,234,235,237 suggesting possible therapeutic alternatives to preterm delivery. Most importantly, risk-stratification methods using antiangiogenic factors have already proven to be safe, efficient, cost-effective, and economical, making them possibilities for improving care in countries that carry the highest mortality from preeclampsia. Disclosures S. Rana reports serving as a consultant for Roche Diagnostics and Thermofisher and has received research funding from Roche and Siemens. Dr Karumanchi is colisted as coinventors on patents related to preeclampsia biomarkers and therapies that are held at Beth Israel Deaconess Medical Center. He has a financial interest in Aggamin LLC and also reports serving as a consultant to Thermofisher.He has received research funding from Siemens. The other authors report no conflicts. References 1. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122:1122–1131. doi: 10.1097/01.AOG.0000437382.03963.88 2. Hogan MC, Foreman KJ, Naghavi M, Ahn SY, Wang M, Makela SM, Lopez AD, Lozano R, Murray CJ. 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