Ullmo et al. BMC Pregnancy and Childbirth (2021) 21:816 https://doi.org/10.1186/s12884-021-04263-w STUDY PROTOCOL Open Access Cardiac dysfunction and remodeling regulated by anti-angiogenic environment in patients with preeclampsia: the ANGIOCOR prospective cohort study protocol Johana Ullmo1,2†, Monica Cruz‑Lemini1,2,3†, Olga Sánchez‑García2,3, Lidia Bos‑Real2,4, Patricia Fernandez De La Llama2,5, Francesca Calero2,5, Carla Domínguez‑Gallardo1,2, Carmen Garrido‑Gimenez1,2, Cristina Trilla1,2, Francesc Carreras‑Costa4, Alessandro Sionis4, Josefina Mora2,6, Álvaro García‑Osuna2,7, Jordi Ordoñez‑Llanos6,7 and Elisa Llurba1,2,3* Abstract Background: Cardiovascular diseases (CVD) are cause of increased morbidity and mortality in spite of advances for diagnosis and treatment. Changes during pregnancy affect importantly the maternal CV system. Pregnant women that develop preeclampsia (PE) have higher risk (up to 4 times) of clinical CVD in the short- and long-term. Predomi‑ nance of an anti-angiogenic environment during pregnancy is known as main cause of PE, but its relationship with CV complications is still under research. We hypothesize that angiogenic factors are associated to maternal cardiac dysfunction/remodeling and that these may be detected by new cardiac biomarkers and maternal echocardiography. Methods: Prospective cohort study of pregnant women with high-risk of PE in first trimester screening, established diagnosis of PE during gestation, and healthy pregnant women (total intended sample size n = 440). Placental bio‑ chemical and biophysical cardiovascular markers will be assessed in the first and third trimesters of pregnancy, along with maternal echocardiographic parameters. Fetal cardiac function at third trimester of pregnancy will be also evalu‑ ated and correlated with maternal variables. Maternal cardiac function assessment will be determined 12 months after delivery, and correlation with CV and PE risk variables obtained during pregnancy will be evaluated. Discussion: The study will contribute to characterize the relationship between anti-angiogenic environment and maternal CV dysfunction/remodeling, during and after pregnancy, as well as its impact on future CVD risk in patients with PE. The ultimate goal is to improve CV health of women with high-risk or previous PE, and thus, reduce the bur‑ den of the disease. Trial registration: NCT04​162236 Keywords: Preeclampsia, Cardiac dysfunction, Cardiac remodeling, sFlt-1, PlGF, Angiogenic factors, Cardiac biomarkers, Cardiovascular risk Background *Correspondence: ellurba@santpau.cat Cardiovascular diseases (CVD) are cause of increased † Johana Ullmo and Monica Cruz-Lemini contributed equally to this work. morbidity and mortality in spite of advances for diag- 1 Obstetrics and Gynecology Department, Santa Creu i Sant Pau University Hospital & Universitat Autònoma, Barcelona, Spain nosis and treatment. Manifestations of CVD, risk fac- Full list of author information is available at the end of the article tors and treatment are different in women than in men; © The Author(s) 2021. 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The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Ullmo et al. BMC Pregnancy and Childbirth (2021) 21:816 Page 2 of 9 women are affected by traditional CVD risk factors, but PlGF is decreased. This occurs due to a combination also by gender-specific ones, such as polycystic ovar- of decreased expression because of poor placentation, ian syndrome or pregnancy-associated disorders such and reduced free PlGF due to sFlt-1 binding [14]. This as preeclampsia (PE) [1]. In 2011, the American Heart leads to an increase in the sFlt-1/PlGF ratio, which has Association (AHA) guideline for preventing CVD in been described as better predictor for PE severity than women included PE, gestational hypertension, diabetes either marker alone [15]. Recently, our group reported mellitus, and systemic autoimmune collagen-vascular an association between angiogenic factors during preg- disease (i.e., lupus or rheumatoid arthritis) as factors nancy and CV disease 12 years post-partum, suggesting associated with increased risk of CVD [2]. Later, in 2018 angiogenic factors are important players in PE-associ- and 2019, the AHA/ACC Multisociety Guideline on the ated CV risk later in life [16]. Management of Blood Cholesterol [3]; and the American In addition to maternal CV effects, fetal cardiac College of Cardiology (ACC)/AHA guidelines [4] intro- programming during pregnancy and its relationship duced the concept of women-specific factors to consider with angiogenic environment has not been previously for risk, diagnosis and treatment of CVD; these factors assessed. Fetal programming refers to the impact on now included PE. fetal health due to intrauterine environment [17]. It One of the most prevalent complications of pregnancy occurs when the fetal environment is modified by an is PE. Epidemiological studies have shown that PE is asso- adverse condition in a critical moment of develop- ciated with development of CV risk factors, hyperten- ment. Pregnancy complications such as PE and intra- sion, myocardial infarction, stroke, renal complications, uterine growth restriction are associated with fetal vascular and metabolic dysfunction during pregnancy programming [18, 19]. However, little is known on and in later years. Pregnant women that develop preec- the role of angiogenic biomarkers for early detection lampsia (PE) have higher risk (up to 4 times) of clini- of fetal cardiac abnormalities and programming in PE cal CVD in the short- and long-term [5, 6]. When PE is pregnancies. accompanied by preterm birth and/or small for gesta- Multiple biomarkers have been assessed to evalu- tional age, the adjusted risk for CVD is increased by 45% ate CVD risk or myocardial damage in PE. Arginine for the next 5 years post-partum [7]; risk comparable to vasopressin (AVP) has been shown to reproduce main that of smoking. Therefore, as history of PE has recently maternal and fetal PE features in animal models [20] been incorporated by the aforementioned societies as an and some studies propose its more stable metabolite, independent risk factor for CVD [8], follow-up starting copeptin, as an early predictor of PE [21]. Thus, AVP within the fourth decade of life is recommended by some concentration is estimated measuring copeptin. Car- authors [9]. All these facts highlight the need to prevent diac troponins (cTn) are isoforms solely produced by and diagnose PE during pregnancy, and follow-up these myocardial cells. When measured by high-sensitivity women after delivery. (hs) methods, cTn can detect small amounts released in Changes during pregnancy affect importantly the myocardial ischemia. Few studies have analyzed hs-cTn maternal CV system, in order to maintain adequate fetal in PE [22]; thus, it remains to be determined whether blood perfusion; maternal cardiac output and heart rate hs-cTn could detect minor myocardial damage in PE increase, while blood pressure and vascular resistances women. Natriuretic peptides are biomarkers of cardiac decrease [10]. In PE, CV adaptation in pregnancy is volume overload, vascular hypertension and myocar- abnormal, exceeding physiological levels, which occurs dial elongation. All these conditions are observed in PE, more frequently if there is a hypertensive disorder before and particularly those of the B-family (B-type natriu- pregnancy. In fact, CV findings in PE resemble those due retic peptide, BNP), have been analyzed in normal and to cardiac diastolic dysfunction; i.e., improper left ventri- hypertensive pregnancies and found to be biomarkers cle (LV) relaxation, increased LV chamber stiffness, and for CV alterations in PE [23]. BNP is synthetized as a increased cardiac filling pressures [11], all of which can prehormone (pro-BNP), which is cleaved to an N-ter- be detected by echocardiography. minal fragment (NT-proBNP), and both are associated PE is also characterized by endothelial dysfunction, with hemodynamic stress and heart failure. which results from an imbalance between maternal We hypothesize that an association exists between circulating angiogenic factors, like pro-angiogenic pla- the anti-angiogenic environment and cardiac dysfunc- cental growth factor (PlGF), and anti-angiogenic fac- tion/remodeling in women at risk for PE during preg- tors such as soluble fms-like tyrosine kinase 1 (sFlt-1) nancy and their offspring, and that this relationship [12]. Placental expression and maternal circulating con- could determine an increased CV risk later in life. centrations of sFlt-1 are increased in PE [13], whereas Ullmo et al. BMC Pregnancy and Childbirth (2021) 21:816 Page 3 of 9 Aims trimester screening protocol [24], which includes reg- Primary aim istration/measurement of maternal risk factors, blood pressure (BP), pregnancy-associated plasma protein A • To determine if a relationship exists between angio- (PAPP-A) and mean uterine artery pulsatility index (UtA- genic environment during pregnancy and the risk of PI), at ­11+ 0 to ­13+ 6 weeks of gestation. The estimated maternal cardiovascular dysfunction and remodeling. sample size for the high-risk group is 280 patients, who will be divided according to the subsequent development of PE: Secondary aims • True PE: women from the high-risk group who – To prospectively assess both biochemical and bio- develop PE (estimated n = 40) physical CV markers in a cohort of patients with risk • False PE: women from the high-risk group who do for PE and in healthy pregnant women, in the first not develop PE (estimated n = 240) and third trimesters of pregnancy. – To determine correlation between angiogenic (PlGF) An additional group of healthy pregnant women with and anti-angiogenic (sFlt-1) factors in maternal first trimester low-risk screening for PE will be recruited serum, and biochemical and imaging markers of (n = 100). cardiac dysfunction and remodeling in patients with Additionally, women with established diagnosis of PE established PE. (n = 60) that were not participating previously in the – To evaluate the relationship between placental and study, will be included at time of diagnosis. The local maternal cardiac biomarkers and fetal cardiac func- research coordinator and/or staff will identify eligi- tion in the third trimester of pregnancy. ble women, invite them to participate, provide written – To determine cardiac dysfunction and metabolic sta- and oral information, and obtain the written informed tus 12 months after delivery in women with PE, and consent. its correlation with CV and PE risk variables obtained during pregnancy. Exclusion criteria – To investigate angiogenesis and CV-related genes in Pregnancies with previous maternal conditions such as placental samples of women with PE and controls, thrombophilia, type-1 diabetes, hyperthyroidism, any by microarray and polymerase chain reaction (PCR) renal disease, severe maternal illness, cytomegalovirus validation. or toxoplasmosis infection, maternal human immuno- – To develop a combined model for prediction of car- deficiency virus infection, previous venous or arterial diovascular risk in PE, that includes placental and thrombotic events, alcohol or illicit drug use, as well as cardiac biomarkers, clinical and echocardiographic multiple pregnancies, major fetal anomaly or chromo- variables. somal anomalies. Methods Procedures and interventions Trial registration Patients will be invited to participate after first trimes- https://​clini​caltr​ials.​gov/​NCT04​162236. ter screening (11-13+ 6 weeks); once they have consented to the study, a maternal echocardiographic evaluation Study design will be performed, and blood and urine samples will be Prospective cohort study which will include the follow- obtained. Patients will be scheduled at third trimester ing patients: pregnant women with high-risk of PE in first (28-32 weeks of pregnancy) for a second maternal echo- trimester screening, established diagnosis of PE during cardiographic evaluation, a fetal functional echocar- gestation, and healthy pregnant women (controls). diographic evaluation and a second blood sample. If a patient develops PE before the scheduled evaluations, all Setting/location studies will be conducted before delivery. At birth, umbil- Santa Creu i Sant Pau University Hospital, Universitat ical cord blood, maternal blood and placental samples Autònoma de Barcelona, Barcelona, Spain. will be obtained for evaluation of biomarkers. Finally, a maternal echocardiographic evaluation will be scheduled Inclusion criteria 12 months after delivery, with final blood and urine sam- Women between 18 and 45 years of age, with singleton ples for biomarker analysis. Figure 1 shows the timeline pregnancies and high-risk for PE according to our first for the planned interventions. Ullmo et al. BMC Pregnancy and Childbirth (2021) 21:816 Page 4 of 9 Fig. 1 Timeline of the planned interventions: ANGIOCOR study. PE, preeclampsia; CV, cardiovascular; BP, blood pressure; UtA-PI, uterine artery pulsatility index Maternal echocardiography Fetal echocardiography Maternal echocardiographic evaluation will be per- Fetal echocardiographic examination will be performed formed at first trimester, 28-32 weeks’ gestation and at 3rd trimester of gestation according to the Interna- 12 months postpartum, by a Cardiologist specialized in tional Society of Ultrasound in Obstetrics and Gyne- cardiac imaging, according to the usual standard proto- cology guideline [26]. Briefly, cardiac axis and situs, col [25]. High-resolution images will be acquired with pericardial effusions, ventricular morphology, veno- Affinity 70G (Philips, Andover, MA, USA) ultrasound atrial, atrioventricular and ventricle-arterial connections, machine, with post-processing analysis with a dedi- size and relationships of left and right ventricular out- cated cardiovascular software, including myocardial flow tracts, ductal and aortic arches, atrial size, interven- strain analysis by 2D speckle-tracking (Philips Auto- tricular septum (IVS) and flow through atrioventricular Strain LV). The following parameters will be evaluated: (AV) and semilunar valves will be evaluated using two- LV dimensions (end-diastolic diameter (EDD), end- dimensional, color and pulsed Doppler ultrasound. Fetal systolic diameter (ESD), end-diastolic volume (EDV), functional echocardiography will include the following end-systolic volume (ESV)) and thickness (interven- parameters according to published methodology [27]: tricular septum (IVS) and posterior wall (PW)), left in the 4-chamber view EDD, ESD, IVS, myocardial wall ventricular ejection fraction (EF) obtained by Teicholz thicknesses in diastole (calculation of SF and EF for each and Simpson methods, LV myocardial deformation ventricle) and cardiothoracic ratio. With pulsed Doppler: (strain) parameters, cardiac output, left atrial volume, early and late peaks of transvalvular filling velocities of Doppler transmitral flow analysis including tissue Dop- left and right ventricles (E/A ratio calculation) [28], aortic pler imaging (TDI) and right heart evaluation including valve and pulmonary valve peak systolic velocities, veloc- ventricular diameters, tricuspid annular ring systolic ity time integrals, and fetal heart rate will be measured, excursion (TAPSE) and TDI of the tricuspid lateral and valve diameters will be acquired in 2D for calculation annulus. of cardiac outputs. With M-mode: mitral annular-plane Ullmo et al. BMC Pregnancy and Childbirth (2021) 21:816 Page 5 of 9 systolic excursion (MAPSE) and TAPSE [29]. Finally, left Secondary outcomes isovolumetric contraction and relaxation times, and ejec- tion time will be measured for calculation of myocardial • Cardiac dysfunction or remodeling in fetuses from performance index, as previously described [30]. mothers at risk for PE or established PE, defined as abnormal cardiac performance in third trimes- Biomarker analyses ter echocardiographic ultrasound assessment and/ All blood samples will be collected without anticoagu- or abnormal cardiac biochemical profile (Copeptin, lants. Biomarkers sFlt-1, PlGF, hs-cTnT and NT-proBNP NT-proBNP, hs-cTnT) in umbilical cord blood at will be measured using automated electrochemilumines- delivery. cence immunoassays on a Cobas E601 platform (Roche • Abnormal BP or lipid profile in the PE group as com- Diagnostics GmbH, Mannheim, Germany). Copeptin will pared to the others, in the first, third trimester of be measured in a KRYPTOR lab instrument by an immu- pregnancy, or at 12 months after delivery. noluminometric assay using two polyclonal antibodies • Development of a combined model for prediction of (BRAHMS, Thermo-Fischer, Germany )[21]. The clinical PE, including biochemical and biophysical markers of laboratory involved in the study performs standard inter- CV and placental dysfunction. nal and external quality controls for biomarkers included • Cardiac and metabolic status at 12 months after in the study. For interpreting observed values we will use delivery and their correlation with cardiac and PE reference values or ranges obtained in previous studies or risk variables obtained during pregnancy. Develop- recommended guidelines. ment of a combined model for prediction of CV risk 12 months after delivery, including biochemical and Ambulatory blood pressure monitoring (ABPM) biophysical markers of CV and placental dysfunction. Blood pressure (BP) measurements will be carried out by a 24-h monitoring with the ABPM 7100 (Welch Allyn, Skaneateles, NY, US) that measures brachial or periph- Statistical analysis eral BP and central BP, in addition to pulse wave veloc- Sample size ity. Peripheral BP will be monitored every 20 min and We have planned a 3 year-period recruitment, consider- central BP every 60 min throughout the 24-h period. ing the number of deliveries at our institution. To obtain Day and night periods will be defined according to wak- an adequate sample, a total of 2800 screenings must be ing and sleeping periods reported by patients. Peripheral performed, assuming there is a 1-to-6 ratio between and central BP monitoring will register systolic, diastolic high-risk cases vs controls. We will include all pregnant and mean BP during day- and night-time periods and the women attending our center for first trimester screen- night/day ratio of the different measurements; peripheral ing and agreeing to participate in the study. They will be measurements will also include heart rate and pulse wave divided into two groups according to their PE risk; we velocity. plan to include 280 pregnancies with high-risk of PE and 100 patients with low-risk of PE, as well as 60 patients Data collection with established PE; we have included an estimated Patients and healthy controls will be asked to complete 10% drop-rate during the study. The study has already a questionnaire including demographic, anthropometric, begun the enrollment; as of 30/09/2021 110 high-risk PE personal and familiar clinical data, with special attention patients, 54 low-risk PE patients and 10 established PE to cardiovascular-related information and PE-related patients have been included. obstetric history (previous PE, fetal growth restriction, abruptio placentae or stillbirth) prior to the examination. Database development and statistical analysis A web-based database will be developed through a Outcome measures restricted website. All variables will be recorded, and the Primary outcome collected data will be coded and processed with adequate Maternal cardiac dysfunction or remodeling in the first precautions to ensure patient confidentiality. Each partic- and third trimesters of pregnancy and 12 months post- ipating physician will receive a login name and password partum, defined as any of the following: to gain access to the web-secured database, with access restricted to clinicians with electronic password. • Abnormal cardiac performance in echocardiographic Once sample collection and laboratory determinations assessments. of biomarkers are finished, we will proceed to evaluation • Abnormal concentrations of cardiac biomarkers and analysis of the results obtained with the aid of the (Copeptin, hs-cTnT, NT-proBNP). Statistics Department at our institution. Measures will Ullmo et al. BMC Pregnancy and Childbirth (2021) 21:816 Page 6 of 9 be normalized to expected values for the respective ges- Pregnancy promotes stressful changes on the maternal tational age. For biomarker measurements without refer- CV system, even in normal conditions. Maternal cardiac ence values in pregnancy, we will obtain reference values output and heart rate increase through the three trimes- from the control population, estimated by linear mod- ters of pregnancy, while blood pressure and vascular eling and describe as multiples of the median (MoM). resistances decrease. Both the sympathetic system and Variables not following a Gaussian distribution will be renin-angiotensin-aldosterone axis are activated and con- log-transformed for analysis. tribute to an increased circulating volume. At a structural For the primary outcome, differences in all registered level, enlargement of the four cardiac chambers and an variables among the three study groups will be evaluated increase of the LV wall mass occur [11]. All these changes at the three evaluation points. Group comparisons will are worsened in PE, exceeding normal adaptation. Taken be performed by analysis of variance (ANOVA), followed together, CV findings seen in PE resemble cardiac dias- by post-hoc tests or Chi-squared tests for proportions. tolic dysfunction, a condition promoting improper LV Associations and confusion variables will be explored by relaxation and increasing LV chamber stiffness, resulting a multivariate approach, using logistic regression models. in increased cardiac filling pressures [10]. For secondary outcomes, descriptive data will be ana- The association between CVD and angiogenic fac- lyzed at all relevant time-points, frequency of altered val- tors has been investigated in non-pregnant popula- ues registered and compared among groups and times. tions. Increased concentrations of PlGF at admission Correlations between biochemical markers, including are associated with worse outcomes in acute coronary angiogenic imbalance, and cardiac dysfunction/remod- syndromes, although PlGF stimulates angiogenesis and eling will be assessed. Diagnostic test parameters (sensi- mediates recovery of cardiac pathologies [34]. Increased tivity, specificity, positive and negative predictive values) sFlt-1 concentrations are related to acute coronary occlu- will be calculated, and Cox proportional-hazards model sion and poor cardiac function in patients with stable will be performed. Univariate and multivariate analysis coronary disease [35], and with development of endothe- will allow identifying which variables can be incorpo- lial vascular dysfunction, myocardial injury and adverse rated to a multivariable model to predict CV risk or dis- CV outcomes in patients with congestive heart failure ease in PE. [35]. As in PE, the use of the sFlt-1/PlGF ratio appears In all analyses, a p value below 0.05 will be considered to be more predictive of adverse outcomes in coronary statistically significant. Data will be analyzed using the artery disease than either biomarker alone [36]. Finally, IBM SPSS Statistics 23 statistical package. although angiogenic factors are critical players in PE endothelial dysfunction, there is no evidence support- Quality control and ethics ing their role as maternal cardiotoxic factors, and CV Study documentation will be saved at least 5 years after risk later in life. A possible explanation could be that completion of the study. Upon request of monitors, audi- maternal cardiac damage in PE is so subtle that it can- tors, Ethics Committee or health authorities, files related not be detected by current imaging techniques; therefore, to the study will be available upon request. the use of cardiac biomarkers may have a role for early detection. Discussion Some studies have shown that hs-cTn is elevated in In the current study, we hypothesize that in PE, anti- pregnant women with hypertension or with PE, com- angiogenic imbalance may be associated to maternal and pared with healthy pregnancies. These are strong pre- fetal cardiac dysfunction and remodeling, and that both dictors for development of both conditions [37] and are conditions could induce myocardial damage detected by related to mean peak arterial BP in asymptomatic PE cardiac biomarkers and imaging techniques. Finally, we patients [38]. Knowing hs-cTn can detect minor myocar- postulate that such cardiac abnormalities could be pre- dial damage like that existing due to ischemia, we shall dictive of future cardiovascular health in patients with assess whether PE causes such damage. In addition to history of PE. hs-cTn, copeptin and natriuretic peptides could be help- PE is a hypertensive disorder in which predominance ful biomarkers for cardiac dysfunction in PE. Copeptin of placental anti-angiogenic factors like sFlt-1 over - concentrations may be increased in PE, because it is not angiogenic factors like PlGF exists [31]. PE increases 2- only a regulator of circulating volume, but also respon- to 4-times maternal risk of CVD; although mechanisms sive to the CV stress associated with the condition [39]. linking PE and CVD are not fully understood [32], PlGF Volume changes and hemodynamic stress are charac- and sFlt-1 are regulators of angiogenesis, a mechanism teristics of pregnancy that are particularly strong in PE. which, if altered, constitutes the basis of several CVD Santillan [20] was the first to report a high sensitivity [33]. and specificity of copeptin to predict PE in the first and Ullmo et al. BMC Pregnancy and Childbirth (2021) 21:816 Page 7 of 9 second trimesters of pregnancy. A recent meta-analysis will probably require much longer follow-up given that has confirmed these findings, extending them to the 3rd the studied population will only include young, pregnant trimester, and showing a correlation between copep- women. However, our aim is to initiate a cohort study of tin concentrations and PE severity [40]. On other hand, patients with high-risk for PE or that develop the disease, secretion of natriuretic peptides is increased in response in order to adequately follow-up in the long-term, as we to increases in BP, cardiac filling volume, cardiac cham- have previously done with other cohorts. Development of ber pressure and dilation [32]; consequently, natriuretic a predictive model of future CVD risk or complications, peptide concentrations are increased in PE [41]. We including clinical and echocardiographic variables, CV believe NT-proBNP concentrations in pregnant women and placental biomarkers, will require further validation may be an earlier and alternative tool to echocardiog- in prospective well-powered studies. Finally, in our study raphy for detecting cardiac function alterations existing we will assess associations between CV findings and in PE. Our study plans to use all information generated angiogenic factors but finding of potential causal links by these biomarkers, along with clinical and echocardi- between both will still require further studies. ographic variables, to develop a CV risk score during a To conclude, this study will provide, for the first time, preeclamptic pregnancy, and at 12 months after delivery. evidence characterizing the association between angio- Studies conducted in patients with heart failure and in genic imbalance and CV dysfunction/remodeling in patients with PE have found a possible common patho- women at risk for or developing PE and, in their off- physiological pathway mediated by angiogenic/anti-angi- spring, both during and after pregnancy. We expect to ogenic placental markers like PIGF and sFlt-1 [42, 43]. provide data supporting the association between abnor- Our group has recently shown that 12 years after delivery, mal angiogenesis and CV dysfunction/remodeling during lower levels of PlGF in pregnancy affected by PE were are pregnancy and fetal life, therefore identifying new ther- associated with worse maternal hemodynamics (higher apeutic targets for future studies aiming to prevent CV BP) and lower high-density lipoprotein cholesterol con- morbidity associated with PE. The goal of this research centrations and with subclinical myocardial dysfunction is to obtain insight in the particular risk factors that link (worse global longitudinal strain) and increased carotid pregnancy and CV health, and thus, reduce the burden of intima-media thickness [16]. The results of this study cor- the disease. roborate that angiogenic imbalance in pregnancies com- plicated by PE is related to a negative impact in future CV Abbreviations risk, long term after pregnancy. These findings compel ABPM: Ambulatory Blood Pressure Monitoring; AV: Atrioventricular; BP: Blood to further study causes of PE and the possibility of pre- pressure; CV: Cardiovascular; CVD: Cardiovascular disease; EDD: End-diastolic diction and prevention. In the present study, we wish to diameter; EDV: End-diastolic volume; EF: Ejection fraction; ESD: End-systolic diameter; ESV: End-systolic volume; HR: Heart rate; hs-cTnT: High-sensitivity assess if an anti-angiogenic profile from the beginning of cardiac troponin T; IVS: Interventricular septum; LV: Left ventricle; LVOT: pregnancy determines CV remodeling, that in turn, pro- Left ventricle outflow tract; MAPSE: Mitral annular-ring systolic excursion; motes PE development and associated CV injury that can NT-proBNP: N-terminal portion of the proBNP natriuretic peptide; PAPP-A: Pregnancy-associated plasma protein A; PlGF: Placental growth factor; PCR: persist after pregnancy, conditioning future CV health. Polymerase chain reaction; PE: Preeclampsia; PW: Posterior wall; sEng: Soluble In addition to maternal assessment, we plan to evaluate endoglin; sFlt-1: Soluble fms-like tyrosine kinase 1; SF: Shortening fraction; fetal cardiac function at the third trimester of pregnancy, TAPSE: Tricuspid annular-ring systolic excursion; TDI: Tissue Doppler imaging; VEGF: Vascular endothelial growth factor; UtA-PI: Uterine artery pulsatility to analyze if there are potential associations between index. maternal CV status and angiogenic factors and occur- rence of fetal cardiac programming. Recently, various Acknowledgements Not applicable. studies have demonstrated the occurrence of a fetal car- diac programming in the growth-restricted fetus, which Authors’ contributions persists into childhood [19]. Furthermore, this fetal car- EL conceived the study. JU, MCL, JOL, CDG, CGG and CT and EL are responsible for designing the study, database, analysis, interpretation of data and dissemi‑ diac remodeling is also present in an independent fash- nating the results. FCC, AS and LBR designed the maternal echocardiographic ion, in pregnancies affected by preeclampsia [18]. Given evaluation part and will perform interpretation of cardiac evaluation. PFL that fetal growth-restriction and PE are clinical expres- and FC designed ABPM evaluation, AGO, JM and OSG determined biomarker analyses to be included in the study. All authors have participated in drafting sions of underlying placental disease, we hypothesize and and approving the final manuscript protocol. plan to analyze whether angiogenic factors will be associ- ated with the existence of cardiac remodeling. Funding This project was supported by public funds obtained in competitive calls with There are potential limitations and considerations of peer review (grant PI19/00702), Instituto de Salud Carlos III - Spanish Ministry the present project. We would only observe subclini- of Health, and by the Maternal and Child Health and Development Network cal CV changes due to the short length of postpartum (SAMID) RD16/0022/0015, Instituto de Salud Carlos III - Spanish Ministry of Health. Dr. Cruz-Lemini is supported by Juan Rodés contract JR19/00047, follow-up (12 months). Clinically evident CV outcomes Instituto de Salud Carlos III - Spanish Ministry of Health. The funding sources Ullmo et al. BMC Pregnancy and Childbirth (2021) 21:816 Page 8 of 9 have no involvement in study design, collection, analysis and interpretation of 7. Cain MA, Salemi JL, Tanner JP, Kirby RS, Salihu HM, Louis JM. Pregnancy as data, or in the writing of this manuscript. a window to future health: maternal placental syndromes and short-term cardiovascular outcomes. Am J Obstet Gynecol. 2016;215(4):484 e481–14. Availability of data and materials https://​doi.​org/​10.​1016/j.​ajog.​2016.​05.​047. Datasets that will be used and analyzed for the presented study will be avail‑ 8. Agarwala A, Michos ED, Samad Z, Ballantyne CM, Virani SS. The Use of able from the corresponding author on reasonable request; they will not be Sex-Specific Factors in the Assessment of Women’s Cardiovas‑ publicly available due to patient confidentiality. cular Risk. Circulation. 2020;141(7):592–9 https://​doi.​org/​10.​1161/​CIRCU​ LATIO​NAHA.​119.​043429. 9. Groenhof TKJ, Zoet GA, Franx A, Gansevoort RT, Bots ML, Groen H, et al. Declarations Trajectory of cardiovascular risk factors after hypertensive disorders of pregnancy. Hypertension. 2019;73(1):171–8. https://​doi.​org/​10.​1161/​ Ethics approval and consent to participate HYPER​TENSI​ONAHA.​118.​11726. The study protocol was approved by the Ethics Research Committee on the 10. Melchiorre K, Sutherland GR, Baltabaeva A, Liberati M, Thilaganathan B. 27th of September 2019, IIBSP-PRE-2019-63; patients will provide written Maternal cardiac dysfunction and remodeling in women with preec‑ informed consent for participation. lampsia at term. Hypertension. 2011;57(1):85–93. https://​doi.​org/​10.​1161/​ HYPER​TENSI​ONAHA.​110.​162321. Consent for publication 11. Sanghavi M, Rutherford JD. Cardiovascular physiology of pregnancy. Not applicable. Circulation. 2014;130(12):1003–8. https://​doi.​org/​10.​1161/​CIRCU​LATIO​ NAHA.​114.​009029. Competing interests 12. Leaños-Miranda A, Navarro-Romero CS, Sillas-Pardo LJ, Ramírez-Valen‑ E.L. reports receiving fees for lectures from Sanofi and serving on the advisory zuela KL, Isordia-Salas I, Jiménez-Trejo LM. Soluble Endoglin as a marker board for Roche Diagnostics. The remaining authors declare that they have no for preeclampsia, its severity, and the occurrence of adverse outcomes. competing interests. Hypertension. 2019;74(4):991–7. https://​doi.​org/​10.​1161/​hyper​tensi​ onaha.​119.​13348. Author details 13. Kaufmann P, Mayhew TM, Charnock-Jones DS. Aspects of human feto‑ 1 Obstetrics and Gynecology Department, Santa Creu i Sant Pau University placental vasculogenesis and angiogenesis. II. Changes during normal Hospital & Universitat Autònoma, Barcelona, Spain. 2 Woman and Perinatal pregnancy. Placenta. 2004;25(2-3):114–26. https://​doi.​org/​10.​1016/j.​place​ Health Research Group, Sant Pau Biomedical Research Institute (IIB-Sant Pau), nta.​2003.​10.​009. Sant Pau University Hospital, Barcelona, Spain. 3 Maternal and Child Health 14. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al. Circulat‑ and Development Network (SAMID), RD16/0022/0015, Instituto de Salud ing angiogenic factors and the risk of preeclampsia. N Engl J Med. Carlos III, Madrid, Spain. 4 Cardiology Department, Santa Creu i Sant Pau 2004;350(7):672–83. https://​doi.​org/​10.​1056/​NEJMo​a0318​84. University Hospital, Barcelona, Spain. 5 Nephrology Department, Hypertension 15. Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennström M, et al. and Prevention of Kidney Damage Unit, Fundació Puigvert, Barcelona, Spain. Predictive value of the sFlt-1:PlGF ratio in women with suspected preec‑ 6 Biochemistry Department, Santa Creu i Sant Pau University Hospital & Univer‑ lampsia. N Engl J Med. 2016;374(1):13–22. https://​doi.​org/​10.​1056/​NEJMo​ sitat Autònoma, Barcelona, Spain. 7 Fundació per la Bioquímica i la Patología a1414​838. Molecular, Biochemistry Department, Santa Creu i Sant Pau University Hospital 16. 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Eur J Obstet Gynecol Reprod Biol 2020;25066-25073. https://doi. org/https://​doi.​org/​10.​1016/j.​ejogrb.​2020.​04.​051. • gold Open Access which fosters wider collaboration and increased citations 41. Ker JA, Soma-Pillay P. NT-proBNP: when is it useful in obstetric medicine? • maximum visibility for your research: over 100M website views per year Obstet Med. 2018;11(1):3–5. https://​doi.​org/​10.​1177/​17534​95x17​736717. 42. Hammadah M, Georgiopoulou VV, Kalogeropoulos AP, Weber M, Wang At BMC, research is always in progress. X, Samara MA, et al. Elevated soluble Fms-like tyrosine Kinase-1 and placental-like growth factor levels are associated with development and Learn more biomedcentral.com/submissions