Next Article in Journal
Loss of Sec-1 Family Domain-Containing 1 (scfd1) Causes Severe Cardiac Defects and Endoplasmic Reticulum Stress in Zebrafish
Previous Article in Journal
The Role of Advanced Glycation End-Product Levels Measured by Skin Autofluorescence in the Development of Mitral Annular Calcification
Previous Article in Special Issue
Quality and Content Concordance of International Clinical Guidelines on Hypertensive Disorders of Pregnancy Using the AGREE II Instrument: An Updated Systematic Review
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCDD
Volume 10
Issue 10
10.3390/jcdd10100407
jcdd-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Importance of Inflammatory and Angiogenic Markers in the Evaluation of Early Cardiovascular Disease Risk in Women with Hypertensive Disorders of Pregnancy

by
Tatjana Maselienė
1,*,
Emilija Struckutė
2,
Rūta Breivienė
2,
Diana Ramašauskaitė
2 and
Vilma Dženkevičiūtė
3
1
Clinics of Internal and Family Medicine, Faculty of Medicine, Vilnius University, LT-01513 Vilnius, Lithuania
2
Clinics of Obstetrics and Gyneacology, Faculty of Medicine, Vilnius University, LT-01513 Vilnius, Lithuania
3
Clinics of Cardiology, Faculty of Medicine, Vilnius University, LT-01513 Vilnius, Lithuania
*
Author to whom correspondence should be addressed.
J. Cardiovasc. Dev. Dis. 2023, 10(10), 407; https://doi.org/10.3390/jcdd10100407
Submission received: 23 August 2023 / Revised: 13 September 2023 / Accepted: 20 September 2023 / Published: 22 September 2023
(This article belongs to the Special Issue Women's Cardiovascular Disease)
Versions Notes

Abstract

:
Background: Women with hypertensive disorders of pregnancy (HDP) have a significantly higher risk of developing cardiovascular diseases later in life. The stratification of this risk using biomarkers during pregnancy can help to identify these women and apply early prevention. Objective: We aimed to determine proinflammatory cytokines and angiogenic markers, echocardiographic parameter changes after delivery and predict early cardiovascular disease risk in women with arterial hypertension and its complications during pregnancy. Methods: We conducted a literature search using the PubMed database for the last ten years. A total of 17 articles were included to our study and full text reviewed. Results: Four out of six studies found higher postpartum Interleukin-6 (IL-6) levels in women with HDP. IL–6 correlated positively with waist circumference, body mass index, and triglycerides, and negatively with high density lipoproteins (HDL). Two out of four studies found higher postpartum tumor necrosis factor alpha (TNF-α) levels in women with HDP but later concentration equalizes. One out of eight studies found higher placental growth factor (PlGF) and two out of eight found more elevated soluble fms-like tyrosine kinase-1 (sFlt-1) in women with HDP. With decreasing PlGF and increasing sFlt-1, common carotid artery intima and media thickness, aortic root diameter, left atrial diameter, left ventricle mass, systolic, diastolic, and mean blood pressure increased, whereas HDL decreased. One out of four studies found higher sFlt-1/PlGF. Conclusion: IL-6 remains significantly higher after delivery. Few studies found higher TNF-α, sFlt-1, PlGF and their ratio postpartum. All studies found a correlation between angiogenic factors, IL-6, and cardiovascular disease risk factors.

1. Introduction

Hypertensive disorders are the main cause of morbidity and mortality among women during pregnancy [1]. Hypertensive disorders of pregnancy (HDP) are chronic hypertension, gestational hypertension, preeclampsia (PE), and eclampsia, which occur in 5–10% of all pregnancies [2]. Based on statistical medical data from the Lithuanian Institute of Hygiene, it has been found that 5.2% of pregnant women in Lithuania experienced hypertensive disorders during pregnancy in 2021. Ranging in severity, hypertensive disorders of pregnancy include chronic hypertension (systolic blood pressure (BP) ≥ 140 mmHg or diastolic BP ≥ 90 mmHg that predates the onset of pregnancy); gestational hypertension (hypertension diagnosed after 20-week 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 new-onset hypertension) [3].
Preeclampsia is a pregnancy disorder characterized by hypertension and systemic endothelial impairment. Globally, PE complicates about 2–8% of all pregnancies [4]. Delivery usually resolves all PE symptoms, but sometimes, PE can start de novo in the postpartum period [3].
Hypertensive disorders of pregnancy are also associated with a higher risk of cardiovascular diseases in the long term [5]. Preeclampsia is associated with a 4.19-fold risk of developing heart failure, 2.5-fold risk of developing coronary heart disease, 1.81-fold risk of stroke, and overall a 2.21-fold risk of death because of cardiovascular diseases (CVD) [6]. However, there is a lack of recommendations and prevention programs for CVD in the postpartum period. Early risk assessment and targeted treatment might prevent future CVD. Studies have shown that women with HDP have different risks of CVD later in life. Compared to late-onset PE, early-onset PE is associated with a higher risk of cardiovascular and cerebrovascular events, hypertension, dyslipidemia, and metabolic syndrome [7]. Furthermore, there is a greater risk of cardiovascular disease (CVD) in women with gestational hypertension (GH) who have both preterm delivery and small for gestational age infants, compared to those with GH alone. [8]. Recurrent preeclampsia is associated with an increased risk of hypertension, ischemic heart disease, heart failure, cerebrovascular accident, and hospitalization due to CVD compared with preeclampsia in a single pregnancy followed by normal pregnancy [9]. Studies about traditional modifiable CVD risk biomarkers are non-homogenous as some of them indicate higher rates of glucose, body mass index (BMI), high density lipoproteins (HDL), low density lipoproteins (LDL), triglycerides in women with HDP. In contrast, others do not find significant differences in these biomarkers between women with HDP and normal pregnancies, postpartum or during pregnancy [10,11,12,13,14]. Using novel biomarkers could help to identify women with a greater risk of CVD.
The mechanism of increased CVD risk is unclear, but there are two possible pathways. The first one is that women with HDP have an increased CVD risk profile before pregnancy as HDP and CVD share some of the same risk factors such as obesity, smoking, alcohol intake, age, diabetes, and family history. The HDP might be the first manifestation of increased CVD risk [15]. The other one is that preeclampsia generates a long-lasting endothelial and cardiac dysfunction contributing to further CVD development [16]. Preeclampsia is a state of chronic inflammation with an immune imbalance where proinflammatory cytokines are increased (TNF-α, IL-6, IL-17) and anti-inflammatory cytokines are reduced (IL-10, IL-4) [17]. TNF-α and IL-6 increase gradually with the severity of preeclampsia from gestational hypertension to mild preeclampsia and severe preeclampsia [18]. Preeclampsia is also associated with placental malperfusion because of inadequate spiral arteries remodeling. Placental hypoxia results in syncytiotrophoblasts dysfunction. In response to hypoxia, syncytiotrophoblasts decrease the production of PlGF and increase the production of sFlt-1. The imbalance of angiogenic factors results in endothelial dysfunction [19]. As these angiogenic and inflammatory factors are involved in the pathogenesis of HDP, they might be useful in early CVD risk stratification for women with HDP and potential therapeutical targets. This narrative review aimed to examine the current knowledge about the association between inflammatory, angiogenic factors and early cardiovascular disease risk.

2. Materials and Methods

The literature search was performed using the PubMed database and included articles since 1 November 2004. The PubMed database was used because of free access from our university. The time frame was 19 years. Arterial hypertension and its complications during pregnancy was the exact object of analysis. After reviewing the database, we selected those pro-inflammatory and angiogenic markers that have been studied the most during pregnancy. Used keywords were placental growth factor, soluble fms—like tyrosine kinase-1, interleukin-6, interleukin-10, tumor necrosis factor alpha, cardiovascular disease risk, hypertensive disorders of pregnancy, and preeclampsia. The database generated 2598 articles. Initial screening was conducted on the basis of the article’s title and abstract screen, followed by full manuscript review in duplicate for articles that appeared to be relevant. Consensus was achieved by three reviewers (E.S., T.M., V.D.) in the event of uncertainty or disagreement. We identified 25 articles to investigate further. Once again, two reviewers (T.M. and E.S.) thoroughly reviewed the full text of the articles and finally included 12 articles in our research. The article selection was performed from December 2021 to February 2022. Unfortunately, we had to exclude 13 articles. We did not include reports that were prospective studies or literature reviews or focused on HDP and other health conditions. We also excluded articles that only measured biomarkers during pregnancy or studied biomarkers triggered by inflammation. If we could not access the full-text version of the article, we did not include it. Ultimately, we added five articles to the list from references and had all 17 articles in our study.

3. Results

All results are listed below in Table 1.

3.1. TNF-α

Preeclampsia is associated with significantly higher levels of the proinflammatory cytokine TNF-α than uncomplicated pregnancies [31]. TNF-α is produced by the placenta and innate immune cells [32]. It is a pro-atherogenic cytokine that promotes atherosclerosis and activates leukocyte adhesion to the endothelium [33]. TNF-α increases during all pregnancy and has been related to miscarriages, fetal losses, preeclampsia, and preterm birth and is associated with IL-10 reduction [34]. There seemed to be an essential antagonistic balance between TNF-α and IL-10 ratio during implantation and pregnancy. Both cytokines were produced by immune cells and trophoblast. An increase in the TNF-α/IL-10 ratio potentially causes early and late pregnancy complications, mostly implantation failure, fetal loss, hypertensive syndromes, and gestational diabetes [35,36,37]. In four case–control studies, researchers examined postpartum TNF-α changes in plasma. Two out of four studies found significantly higher levels of TNF-α in women with a history of HDP compared to uncomplicated pregnancies [11,22]. Preeclamptic women 12–14 weeks postpartum had significantly higher levels of TNF-α than those with normotensive pregnancy [22]. Another study found significantly higher TNF-α in pregnancies complicated by hypertensive disorders one year postpartum [11]. Two studies showed no significant differences between case–control TNF-α plasma levels measured 3, 9 months, and 9–16 years postpartum [10,26]. The inconsistency among the studies might be due to the fact that TNF alpha levels decrease over time in the postpartum period. One study grouped patients with a history of HDP together with women who had preterm and small-for-gestational-age newborns. Additionally, there was a small number of participants.

3.2. IL-6

IL-6 is a proinflammatory cytokine secreted excessively by maternal immune cells in preeclampsia [38]. The IL-6 and TNF-α cytokines increase vascular permeability and induce apoptosis of trophoblastic cells [39]. IL-6 also acts as a pro-fibrotic factor and stimulates cardiac fibrosis [40]. Chronic elevation of IL-6 induces myocardial hypertrophy and decreases contractility [41]. IL-6 is expressed in carotid atherosclerotic plaques. Also, circulating levels of IL-6 are higher in patients with atherosclerotic plaques than those without [42]. Of the six case–control studies, four found elevated postpartum IL-6 levels in pregnancies complicated by hypertensive disorders. Significantly higher IL-6 levels were discovered 12–14 weeks after delivery in preeclamptic women than in controls [22]. IL-6 levels were higher among women with cardiovascular disease related pregnancy complications (hypertensive disorder of pregnancy, preterm birth, and small for gestational age baby) 3 and 9 months postpartum [10]. A total of 9–16 years postpartum plasma level of IL-6 was higher in the early-onset preeclampsia group than in the uncomplicated pregnancy group [26]. IL-6 levels were also higher among women with a history of HDP than normotensive pregnancies 12–22 years postpartum [29]. Another two studies did not find any significant difference in IL-6 in case–control groups one year and twenty years postpartum [11,30] but found elevated IL-6/IL-10 ratio 20 years postpartum in the HDP group [30]. Researchers found that IL-6 measured 9–16 years postpartum in women with a history of early-onset preeclampsia relates to metabolic syndrome features such as waist circumference, BMI, fasting triglycerides, and fasting HDL cholesterol [26].

3.3. Angiogenic Factors

Placental growth factor (PlGF) is a proangiogenic factor secreted mostly by the placenta. The main function of PlGF is placental vascularization. During HDP, the secretion of PlGF decreases, resulting in hypertension. Soluble fms-like tyrosine kinase-1 (sFlt-1) is an anti-angiogenic factor that binds to PlGF and reduces availability. Decreased PlGF and increased sFlt-1 result in endothelial dysfunction and impaired hemodynamics [16]. In two of eight case–control studies, researchers found higher postpartum sFlt-1 levels in women with a history of HDP compared to the control group. One year postpartum, sFlt-1 decreased in both preeclampsia and control groups but remained significantly higher in the preeclampsia group. Also, women with PE had a higher sFlt-1/PlGF ratio [24]. Five to eight years postpartum, sFlt-1 levels were higher in the PE group before and after adjustment for BMI, but p-value was marginal, equal to 0.05 [25].Only one study of eight found higher PlGF serum levels three months postpartum in women with a history of HDP [23]. Decreased PlGF levels are associated with higher systolic, and diastolic, mean blood pressure and lower HDL [14,28]. Higher sFlt-1 levels measured in preeclamptic women during their pregnancy correlate with higher mean arterial pressure 12 years postpartum, but there was no correlation between sFlt-1 and BMI [43]. The higher sFlt-1 and sFlt-1/PlGF were during pregnancy, the lower HDL was 12 years postpartum [28].

3.4. Traditional Cardiovascular Risk Factors

Findings about traditional cardiovascular risk factors in preeclamptic patients are nonhomogenous. Researchers found that HDL, LDL, total cholesterol, TAG and calprotectin did not differ in PE group compared to control group, but high sensitivity C-reactive protein, mean arterial pressure, systolic blood pressure were found to be higher in PE patients 5–8 years postpartum [25]. At 12 years postpartum, PE patients had more cases of dyslipidemia and arterial hypertension compared to control patients, but there were no significant difference in body mass index (BMI), smoking status, metabolic syndrome, glucose, LDL, total cholesterol, and TAG [28].

3.5. Arterial Aging Signs and Angiogenic Factors

The extent of atherosclerotic plaques can be evaluated by measuring common carotid artery intima-media thickness (cIMT). This test works as a subclinical marker of atherosclerosis progression. Thicker intima, thinner media, and a higher intima-media ratio (I/M) were found in women with preeclampsia compared to normal pregnancies during diagnosis [24]. sFlt-1 and sFlt-1/PlGF correlated positively and PlGF negatively with intima thickness and intima-media ratio during diagnosis and one year postpartum [24]. After adjusting for BMI, blood pressure, smoking status, and family history of CVD, the correlation between angiogenic factors and arterial wall measurements remained significant [24]. The same research found that higher sFlt-1 and sFlt-1/PlGF ratio were associated with higher BMI and blood pressure [24]. Angiogenic factors measured during pregnancy correlated with cIMT 12 years postpartum, sFlt-1 correlated positively, and PlGF negatively [28]. Also, cIMT was higher in the preeclampsia group than in controls 12 years postpartum [28]. All changes are listed below in Table 2.

3.6. Angiogenic Factors and Echocardiogram Measurements

Left ventricle global longitudinal strain (LV GLS) measures left ventricle systolic function indicating subclinical left ventricle dysfunction [44]. LV GLS indicates the maximal shortening of myocardial longitudinal length during systole compared to the resting length in diastole [45]. GLS was worse in women with preeclampsia than those with chronic or gestational hypertension and those with normotensive pregnancy. Also, sFlt-1 levels correlated with worse GLS at the time of diagnosis of preeclampsia [43]. Higher sFlt-1 levels were measured when severe preeclampsia was diagnosed and were associated with worse LV GLS 4–12 weeks postpartum [21]. PlGF during pregnancy correlated negatively with GLS. sFlt-1 correlates positively with left ventricular posterior wall thickness [28]. Elevated sFlt-1 levels detected during pregnancy were associated with increased chamber and vascular stiffness measurements (such as end systolic elastance, and arterial elastance) during pregnancy and 4–12 weeks postpartum. Higher sFlt-1 levels were associated with the worse diastolic function (higher E/E’ at the time of diagnosis, decreased E/A at the time of diagnosis, and 4–12 weeks postpartum) [21]. Laura Benschop et al., found that individuals with lower mid-pregnancy PlGF levels had larger aortic root diameter, left atrial diameter, and left ventricular mass six years postpartum. The study included women with a history of HDP and individuals from all populations. Results persisted the same after excluding women with complicated pregnancies [14]. Increased levels of sFlt-1 measured during pregnancy correlated with increased left ventricular mass, but there was no correlation with ejection fraction [43]. All changes are listed below in Table 3 and Table 4.

4. Discussion

Hypertensive disorders of pregnancy are associated with increased cardiovascular disease (CVD) risk later in life. The American Heart Association identifies preeclampsia and gestational hypertension as CVD risk factors [46]. The diagnosis of HDP might be an opportunity for risk stratification and targeted prevention of CVD, but the risk stratification and treatment methods currently need to be improved. The researchers found that angiogenic factors measured during the pregnancy correlate with CVD risk factors (blood pressure, arterial aging signs, HDL, cardiac remodeling) evaluated postpartum. Also, in most studies, authors found no significant difference between women with a history of HDP and normal pregnancies in the postpartum levels of angiogenic factors. During pregnancy, it is important to measure angiogenic factors not only to predict preeclampsia but also to stratify the risk of cardiovascular disease. As angiogenic factors equalize after pregnancy between women with HDP and normal pregnancies, they might not contribute to postpartum CVD development.
It is necessary to include more details regarding specific levels of angiogenic factors and how they relate to the risk of cardiovascular disease. Laura Benschop et al., in their study, divided PlGF into quartiles and found that the lowest quartile had the highest chance of being evaluated by blood pressure and echocardiography [14]. Also, the best time for biomarkers measurement during pregnancy is unknown. However, Rugina I. Neuman et al., found that sFlt-1, PlGF, and their ratio cannot predict hypertension one year postpartum [47].
The relationship between biomarkers and subsequent cardiovascular events and mortality in women with a history of HDP is unclear. However, increased levels of sFlt-1 and decreased PlGF are found in heart failure, and they are significantly related to New York Heart Association (NYHA) classes (p < 0.001) [48]. Higher sFlt-1 levels are associated with atherosclerotic cardiovascular disease events (cardiovascular death, myocardial infarction, stroke, revascularization) [49]. It was shown that patients with acute decompensated heart failure and higher PlGF had worse prognosis than the low PlGF patients in terms of all-cause and cardiovascular death [50]. Anti-TNF-α therapy in rheumatoid arthritis patients reduces the risk of all cardiovascular events (myocardial infarction, cerebrovascular accident, congestive heart failure) [51]. Patients with heart failure, who had higher levels of TNF-α, were found to have a lower survival rate [32]. Acute coronary syndrome patients in the highest quartile of IL-6 have a higher risk of cardiovascular events and death [52]. To our best knowledge, there are no studies between biomarkers and future cardiovascular events and mortality in women with history of HDP.
Discussed biomarkers might give an additional value when evaluating cardiovascular events risk, not only in pregnant women. The use of both BNP and PlGF improves prediction of cardiovascular events in chronic kidney disease patients compared to BNP alone [53]. High placental growth factor levels can indicate increased cardiac risk in patients with undetectable, low, and high troponin T levels [54]. sFlt-1 and PlGF correlate with cardiovascular risk factors such as galectin-3, PTH, and aldosterone, sFlt-1 correlates with NT-proBNP [48]. Other researchers found correlation between sFlt-1 and D-dimers, but not with NT-proBNP [49]. BNP and troponin I were shown to exhibit the strongest association and sFlt-1 exhibited the next strongest association in a study which evaluated relationship between 9 biomarkers and hospitalization in heart failure patients [55]. The biomarkers discussed in our article could be an excellent indicator for further cardiovascular risk assessment, but additional studies are needed.
Echocardiographic changes can also be used to predict cardiovascular diseases. Cardiac function and morphology do not change immediately before the delivery and early postpartum period [56]. Victoria A. deMartelly et al., found that GLS, left ventricular posterior wall thickness, and interventricular septal thickness stay elevated ten years postpartum in preeclamptic women [57]. Chahinda Ghossein-Doha et al., found that chronic hypertension diagnosed six years postpartum was associated with increased left ventricular mass index and diastolic blood pressure at nine months postpartum [58].
Our exploration indicates that women with a history of HDP have higher levels of IL-6 after delivery, and these elevated levels can persist for up to 12–22 years. To our knowledge, no other studies evaluated IL-6 levels for a period longer than 22 years postpartum. High TNF-α levels have also been linked to the development of cardiovascular disease. As IL-6 and TNF-α play a role in cardiovascular disease pathogenesis, they might be useful as therapeutic targets. MgSO4 and nifedipine reduced the circulating levels of IL-6 and TNF-α in preeclamptic women [59,60]. Other studies found that IL-6 levels can be reduced by methotrexate, anakinra, and canakinumab, but none of them have been conducted on women with a history of HDP [61,62,63].
Laura Ormesher et al., examined echocardiographic measurements of women with a history of preterm preeclampsia treated with enalapril for six months postpartum [64]. The study found no difference between the case and control groups at six months postpartum [64]. However, women treated with enalapril had better diastolic function and left ventricular remodeling [64]. These findings suggest that enalapril treatment may reduce the long-term risk of cardiovascular disease.
According to these findings, cytokines can be used as biomarkers to predict and manage preeclampsia in its early stages. Echocardiographic changes can also indicate cardiovascular disease later in life. However, just using echocardiography to assess cardiovascular risk during pregnancy or after delivery is not advisable.
The small number of included studies limited our review. Because of the lack of studies and high variation of the biomarkers measurement’s timing, it was impossible to make a meta-analysis. To evaluate the cardiovascular risk in women, it is necessary to conduct more studies that examine changes in cytokines, angiogenic factors, and echocardiographic parameters during pregnancy and postpartum.

Author Contributions

Conceptualization, V.D., D.R. and T.M., methodology, T.M. and E.S.; formal analysis, T.M., E.S. and R.B.; resources, T.M. and E.S.; data curation, T.M.; writing—original draft preparation, T.M. and E.S.; writing—review and editing, T.M.; visualization, T.M.; supervision, V.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Khedagi, A.M.; Bello, N.A. Hypertensive Disorders of Pregnancy. Cardiol. Clin. 2021, 39, 77–90. [Google Scholar] [CrossRef] [PubMed]
  2. Hutcheon, J.A.; Lisonkova, S.; Joseph, K.S. Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy. Best. Pract. Res. Clin. Obs. Gynaecol. 2011, 25, 391–403. [Google Scholar] [CrossRef] [PubMed]
  3. Rana, S.; Lemoine, E.; Granger, J.P.; Karumanchi, S.A. Preeclampsia: Pathophysiology, Challenges, and Perspectives. Circ. Res. 2019, 124, 1094–1112. [Google Scholar] [CrossRef] [PubMed]
  4. Steegers, E.A.P.; von Dadelszen, P.; Duvekot, J.J.; Pijnenborg, R. Pre-Eclampsia. Lancet 2010, 376, 631–644. [Google Scholar] [CrossRef] [PubMed]
  5. Coutinho, T.; Lamai, O.; Nerenberg, K. Hypertensive Disorders of Pregnancy and Cardiovascular Diseases: Current Knowledge and Future Directions. Curr. Treat. Options Cardiovasc. Med. 2018, 20, 56. [Google Scholar] [CrossRef] [PubMed]
  6. Wu, P.; Haththotuwa, R.; Kwok, C.S.; Babu, A.; Kotronias, R.A.; Rushton, C.; Zaman, A.; Fryer, A.A.; Kadam, U.; Chew-Graham, C.A.; et al. Preeclampsia and Future Cardiovascular Health. Circ. Cardiovasc. Qual. Outcomes 2017, 10, e003497. [Google Scholar] [CrossRef]
  7. Dall’Asta, A.; D’Antonio, F.; Saccone, G.; Buca, D.; Mastantuoni, E.; Liberati, M.; Flacco, M.E.; Frusca, T.; Ghi, T. Cardiovascular events following pregnancy complicated by pre-eclampsia with emphasis on comparison between early- and late-onset forms: Systematic review and meta-analysis. Ultrasound Obstet. Gynecol. 2021, 57, 698–709. [Google Scholar] [CrossRef]
  8. Riise, H.K.R.; Sulo, G.; Tell, G.S.; Igland, J.; Nygård, O.; Iversen, A.C.; Daltveit, A.K. Association Between Gestational Hypertension and Risk of Cardiovascular Disease Among 617 589 Norwegian Women. J. Am. Heart Assoc. 2018, 7, e008337. [Google Scholar] [CrossRef]
  9. Brouwers, L.; van der Meiden-van Roest, A.J.; Savelkoul, C.; Vogelvang, T.E.; Lely, A.T.; Franx, A.; van Rijn, B.B. Recurrence of pre-eclampsia and the risk of future hypertension and cardiovascular disease: A systematic review and meta-analysis. BJOG 2018, 125, 1642–1654. [Google Scholar] [CrossRef]
  10. Parikh, N.I.; Laria, B.; Nah, G.; Singhal, M.; Vittinghoff, E.; Vieten, C.; Stotland, N.; Coleman-Phox, K.; Adler, N.; Albert, M.A.; et al. Cardiovascular Disease-Related Pregnancy Complications Are Associated with Increased Maternal Levels and Trajectories of Cardiovascular Disease Biomarkers During and After Pregnancy. J. Womens Health 2020, 29, 1283–1291. [Google Scholar] [CrossRef]
  11. Ehrenthal, D.B.; Rogers, S.; Goldstein, N.D.; Edwards, D.G.; Weintraub, W.S. Cardiovascular Risk Factors One Year after a Hypertensive Disorder of Pregnancy. J. Womens Health 2015, 24, 23–29. [Google Scholar] [CrossRef]
  12. Östlund, E.; Al-Nashi, M.; Hamad, R.R.; Larsson, A.; Eriksson, M.; Bremme, K.; Kahan, T. Normalized endothelial function but sustained cardiovascular risk profile 11 years following a pregnancy complicated by preeclampsia. Hypertens. Res. 2013, 36, 1081–1087. [Google Scholar] [CrossRef] [PubMed]
  13. Escouto, D.C.; Green, A.; Kurlak, L.; Walker, K.; Loughna, P.; Chappell, L.; Pipkin, F.B.; Bramham, K. Postpartum evaluation of cardiovascular disease risk for women with pregnancies complicated by hypertension. Pregnancy Hypertens. 2018, 13, 218–224. [Google Scholar] [CrossRef] [PubMed]
  14. Benschop, L.; Duvekot, J.J.; Roeters van Lennep, J.E. Future risk of cardiovascular disease risk factors and events in women after a hypertensive disorder of pregnancy. Heart 2019, 105, 1273–1278. [Google Scholar] [CrossRef]
  15. Umesawa, M.; Kobashi, G. Epidemiology of hypertensive disorders in pregnancy: Prevalence, risk factors, predictors and prognosis. Hypertens. Res. 2017, 40, 213–220. [Google Scholar] [CrossRef]
  16. Hong, K.; Kim, S.H.; Cha, D.; Park, H. Defective Uteroplacental Vascular Remodeling in Preeclampsia: Key Molecular Factors Leading to Long Term Cardiovascular Disease. Int. J. Mol. Sci. 2021, 22, 11202. [Google Scholar] [CrossRef]
  17. Harmon, A.C.; Cornelius, D.C.; Amaral, L.M.; Faulkner, J.L.; Cunningham, M.W., Jr.; Wallace, K.; LaMarca, B. The role of inflammation in the pathology of preeclampsia. Clin. Sci. 2016, 130, 409–419. [Google Scholar] [CrossRef] [PubMed]
  18. Wang, Y.; Shi, D.; Chen, L. Lipid profile and cytokines in hypertension of pregnancy: A comparison of preeclampsia therapies. J. Clin. Hypertens. 2018, 20, 394–399. [Google Scholar] [CrossRef]
  19. Redman, C.W.G.; Staff, A.C. Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity. Am. J. Obstet. Gynecol. 2015, 213, S9.e1–S9.e4. [Google Scholar] [CrossRef]
  20. Perni, U.; Sison, C.; Sharma, V.; Helseth, G.; Hawfield, A.; Suthanthiran, M.; August, P. Angiogenic Factors in Superimposed Preeclampsia. Hypertension 2012, 59, 740–746. [Google Scholar] [CrossRef]
  21. Levine, L.; Arany, Z.; Kern-Goldberger, A.; Koelper, N.; Lewey, J.; Sammel, M.D.; Elovitz, M.A.; Ky, B. Soluble Flt1 levels are associated with cardiac dysfunction in Black women with and without severe preeclampsia. Hypertens. Pregnancy 2021, 40, 44–49. [Google Scholar] [CrossRef] [PubMed]
  22. Vitoratos, N.; Economou, E.; Iavazzo, C.; Panoulis, K.; Creatsas, G. Maternal Serum Levels of TNF-Alpha and IL-6 Long after Delivery in Preeclamptic and Normotensive Pregnant Women. Mediators Inflamm. 2010, 2010, 908649. [Google Scholar] [CrossRef] [PubMed]
  23. Noori, M.; Donald, A.E.; Angelakopoulou, A.; Hingorani, A.D.; Williams, D.J. Prospective Study of Placental Angiogenic Factors and Maternal Vascular Function Before and After Preeclampsia and Gestational Hypertension. Circulation 2010, 122, 478–487. [Google Scholar] [CrossRef] [PubMed]
  24. Akhter, T.; Wikström, A.K.; Larsson, M.; Larsson, A.; Wikström, G.; Naessen, T. Association between angiogenic factors and signs of arterial aging in women with pre-eclampsia. Ultrasound Obs. Gynecol. 2017, 50, 93–99. [Google Scholar] [CrossRef] [PubMed]
  25. Kvehaugen, A.S.; Dechend, R.; Ramstad, H.B.; Troisi, R.; Fugelseth, D.; Staff, A.C. Endothelial function and circulating biomarkers are disturbed in women and children after preeclampsia. Hypertension 2011, 58, 63–69. [Google Scholar] [CrossRef] [PubMed]
  26. Bokslag, A.; Franssen, C.; Alma, L.J.; Kovacevic, I.; van Kesteren, F.; van Teunissen, P.W.; Kamp, O.; Ganzevoort, W.; Hordijk, P.L.; de Groot, M.; et al. Early-onset preeclampsia predisposes to preclinical diastolic left ventricular dysfunction in the fifth decade of life: An observational study. PLoS ONE 2018, 13, e0198908. [Google Scholar] [CrossRef]
  27. Gaugler-Senden, I.P.M.; Tamsma, J.T.; van der Bent, C.; Kusters, R.; Steegers, E.A.P.; de Groot, C.J.M. Angiogenic factors in women ten years after severe very early onset preeclampsia. PLoS ONE. 2012, 7, e43637. [Google Scholar] [CrossRef]
  28. Garrido-Gimenez, C.; Mendoza, M.; Cruz-Lemini, M.; Galian-Gay, L.; Sanchez-Garcia, O.; Granato, C.; Rodriguez-Sureda, V.; Rodriguez-Palomares, J.; Carreras-Moratonas, E.; Cabero-Roura, L.; et al. Angiogenic Factors and Long-Term Cardiovascular Risk in Women That Developed Preeclampsia During Pregnancy. Hypertension 2020, 76, 1808–1816. [Google Scholar] [CrossRef]
  29. Tanz, L.J.; Stuart, J.J.; Missmer, S.A.; Rimm, E.B.; Sumner, J.A.; Vadnais, M.A.; Rich-Edwards, J.W. Cardiovascular biomarkers in the years following pregnancies complicated by hypertensive disorders or delivered preterm. Pregnancy Hypertens. 2018, 13, 14–21. [Google Scholar] [CrossRef]
  30. Freeman, D.J.; McManus, F.; Brown, E.A.; Cherry, L.; Norrie, J.; Ramsay, J.E.; Clark, P.; Walker, I.D.; Sattar, N.; Greer, I.A. Short- and Long-Term Changes in Plasma Inflammatory Markers Associated With Preeclampsia. Hypertension 2004, 44, 708–714. [Google Scholar] [CrossRef]
  31. Black, K.D.; Horowitz, J.A. Inflammatory Markers and Preeclampsia: A Systematic Review. Nurs. Res. 2018, 67, 242–251. [Google Scholar] [CrossRef]
  32. Alijotas-Reig, J.; Esteve-Valverde, E.; Ferrer-Oliveras, R.; Llurba, E.; Gris, J.M. Tumor Necrosis Factor-Alpha and Pregnancy: Focus on Biologics. An Updated and Comprehensive Review. Clin. Rev. Allerg. Immunol. 2017, 53, 40–53. [Google Scholar] [CrossRef] [PubMed]
  33. Tousoulis, D.; Oikonomou, E.; Economou, E.K.; Crea, F.; Kaski, J.C. Inflammatory cytokines in atherosclerosis: Current therapeutic approaches. Eur. Heart J. 2016, 37, 1723–1732. [Google Scholar] [CrossRef] [PubMed]
  34. Alijotas-Reig, J.; Llurba, E.; Gris, J.M. Potentiating maternal immune tolerance in pregnancy: A new challenging role for regulatory T cells. Placenta 2014, 35, 241–248. [Google Scholar] [CrossRef]
  35. Majetschak, M.; Obertacke, U.; Schade, F.U.; Bardenheuer, M.; Voggenreiter, G.; Bloemeke, B.; Michael, H. Tumor necrosis factor gene polymorphisms, leukocyte function, and sepsis susceptibility in blunt trauma patients. Clin. Diagn. Lab. Immunol. 2002, 9, 1205–1211. [Google Scholar] [CrossRef] [PubMed]
  36. Wedekind, L.; Belkacemi, L. Altered cytokine network in gestational diabetes mellitus affects maternal insulin and placental-fetal development. J. Diabetes Complicat. 2016, 30, 1393–1400. [Google Scholar] [CrossRef]
  37. Quenby, S.; Bates, M.; Doig, T.; Brewster, J.; Lewis-Jones, D.I.; Johnson, P.M.; Vince, G. Pre-implantation endometrial leukocytes in women with recurrent miscarriage. Hum. Reprod. 1999, 14, 2386–2391. [Google Scholar] [CrossRef]
  38. Leibowitz, A.; Schiffrin, E.L. Immune mechanisms in hypertension. Curr. Hypertens. Rep. 2011, 13, 465–472. [Google Scholar] [CrossRef]
  39. Chen, L.M.; Liu, B.; Zhao, H.B.; Stone, P.; Chen, Q.; Chamley, L. IL-6, TNFα and TGFβ Promote Nonapoptotic Trophoblast Deportation and Subsequently Causes Endothelial Cell Activation. Placenta 2010, 31, 75–80. [Google Scholar] [CrossRef]
  40. Mohseni, Z.; Derksen, E.; Oben, J.; Al-Nasiry, S.; Spaanderman, M.E.A.; Ghossein-Doha, C. Cardiac dysfunction after preeclampsia; an overview of pro- and anti-fibrotic circulating effector molecules. Pregnancy Hypertens. 2021, 23, 140–154. [Google Scholar] [CrossRef]
  41. Fontes, J.A.; Rose, N.R.; Čiháková, D. The varying faces of IL-6: From cardiac protection to cardiac failure. Cytokine 2015, 74, 62–68. [Google Scholar] [CrossRef] [PubMed]
  42. Ziegler, L.; Lundqvist, J.; Dreij, K.; Wallén, H.; de Faire, U.; Paulsson-Berne, G.; Hedin, U.; Matic, L.; Gigante, B. Expression of Interleukin 6 signaling receptors in carotid atherosclerosis. Vasc. Med. 2021, 26, 3–10. [Google Scholar] [CrossRef] [PubMed]
  43. Shahul, S.; Medvedofsky, D.; Wenger, J.B.; Nizamuddin, J.; Brown, S.M.; Bajracharya, S.; Salahuddin, S.; Thadhani, R.; Mueller, A.; Tung, A.; et al. Circulating Antiangiogenic Factors and Myocardial Dysfunction in Hypertensive Disorders of Pregnancy. Hypertension 2016, 67, 1273–1280. [Google Scholar] [CrossRef] [PubMed]
  44. Abou, R.; Bijl P van der Bax, J.J.; Delgado, V. Global longitudinal strain: Clinical use and prognostic implications in contemporary practice. Heart 2020, 106, 1438–1444. [Google Scholar] [CrossRef]
  45. Chiu, D.; Green, D.; Kalra, P.; Abidin, N. 128 Abnormal Global Longitudinal Strain is Associated with All-Cause Mortality in Haemodialysis Patients. Heart 2016, 102 (Suppl. S6), A90–A91. [Google Scholar] [CrossRef]
  46. Mosca, L.; Benjamin, E.J.; Berra, K.; Bezanson, J.L.; Dolor, R.J.; Lloyd-Jones, D.M.; Newby, L.K.; Piña, I.L.; Roger, V.L.; Shaw, L.J.; et al. Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women—2011 Update: A Guideline From the American Heart Association. J. Am. Coll. Cardiol. 2011, 57, 1404–1423. [Google Scholar] [CrossRef]
  47. Neuman, R.I.; Figaroa, A.M.J.; Nieboer, D.; Saleh, L.; Verdonk, K.; Danser, A.H.J.; Duvekot, H.J.J.; van den Meiracker, A.H.; van Lennep, J.R.; Visser, W. Angiogenic markers during preeclampsia: Are they associated with hypertension 1 year postpartum? Pregnancy Hypertens. 2021, 23, 116–122. [Google Scholar] [CrossRef]
  48. Gruson, D.; Hermans, M.P.; Ferracin, B.; Ahn, S.A.; Rousseau, M.F. Sflt-1 in heart failure: Relation with disease severity and biomarkers. Scand. J. Clin. Lab. Investig. 2016, 76, 411–416. [Google Scholar] [CrossRef]
  49. Mauricio, R.; Singh, K.; Sanghavi, M.; Ayers, C.R.; Rohatgi, A.; Vongpatanasin, W.; de Lemos, J.A.; Khera, A. Soluble Fms-like tyrosine kinase-1 (sFlt-1) is associated with subclinical and clinical atherosclerotic cardiovascular disease: The Dallas Heart Study. Atherosclerosis 2022, 346, 46–52. [Google Scholar] [CrossRef]
  50. Nakada, Y.; Kawakami, R.; Matsui, M.; Ueda, T.; Nakano, T.; Nakagawa, H.; Nishida, T.; Onoue, K.; Soeda, T.; Okayama, S.; et al. Value of Placental Growth Factor as a Predictor of Adverse Events During the Acute Phase of Acute Decompensated Heart Failure. Circ. J. 2019, 83, 395–400. [Google Scholar] [CrossRef]
  51. Systematic Review and Meta-Analysis: Anti–Tumor Necrosis Factor α Therapy and Cardiovascular Events in Rheumatoid Arthritis. Available online: https://onlinelibrary.wiley.com/doi/10.1002/acr.20371 (accessed on 3 July 2022).
  52. Fanola, C.L.; Morrow, D.A.; Cannon, C.P.; Jarolim, P.; Lukas, M.A.; Bode, C.; Hochman, J.S.; Goodrich, E.L.; Braunwald, E.; O’Donoghue, M.L. Interleukin-6 and the Risk of Adverse Outcomes in Patients After an Acute Coronary Syndrome: Observations From the SOLID-TIMI 52 (Stabilization of Plaque Using Darapladib-Thrombolysis in Myocardial Infarction 52) Trial. J. Am. Heart Assoc. 2017, 6, e005637. [Google Scholar] [CrossRef] [PubMed]
  53. Matsui, M.; Uemura, S.; Takeda, Y.; Samejima, K.I.; Matsumoto, T.; Hasegawa, A.; Tsushima, H.; Hoshino, E.; Ueda, T.; Morimoto, K.; et al. Placental Growth Factor as a Predictor of Cardiovascular Events in Patients with CKD from the NARA-CKD Study. J. Am. Soc. Nephrol. 2015, 26, 2871–2881. [Google Scholar] [CrossRef]
  54. Heeschen, C.; Dimmeler, S.; Fichtlscherer, S.; Hamm, C.W.; Berger, J.; Simoons, M.L.; Zeiher, A.M.; CAPTURE Investigators. Prognostic Value of Placental Growth Factor in Patients With Acute Chest Pain. JAMA 2004, 291, 435–441. [Google Scholar] [CrossRef] [PubMed]
  55. Vorovich, E.; French, B.; Ky, B.; Goldberg, L.; Fang, J.C.; Sweitzer, N.K.; Cappola, T.P. Biomarker predictors of cardiac hospitalization in chronic heart failure: A recurrent event analysis. J. Card. Fail. 2014, 20, 569–576. [Google Scholar] [CrossRef] [PubMed]
  56. Giorgione, V.; O’Driscoll, J.; Coutinho, C.M.; Di Fabrizio, C.; Sharma, R.; Khalil, A.; Thilaganathan, B. Peripartum echocardiographic changes in women with hypertensive disorders of pregnancy. Ultrasound Obstet. Gynecol. 2022, 59, 365–370. [Google Scholar] [CrossRef]
  57. deMartelly, V.A.; Dreixler, J.; Tung, A.; Mueller, A.; Heimberger, S.; Fazal, A.A.; Naseem, H.; Lang, R.; Kruse, E.; Yamat, M.; et al. Long-Term Postpartum Cardiac Function and Its Association With Preeclampsia. J. Am. Heart Assoc. 2021, 10, e018526. [Google Scholar] [CrossRef]
  58. Ghossein-Doha, C.; Peeters, L.; van Heijster, S.; van Kuijk, S.; Spaan, J.; Delhaas, T.; Spaanderman, M. Hypertension After Preeclampsia Is Preceded by Changes in Cardiac Structure and Function. Hypertension 2013, 62, 382–390. [Google Scholar] [CrossRef]
  59. Bernstein, H.; Sugimoto, J.; Suzuki-Kakisaka, H.; Romani, A. 823: Magnesium decreases inflammatory cytokine production: A novel innate immunomodulatory mechanism. Am. J. Obstet. Gynecol. 2012, 206, S361. [Google Scholar] [CrossRef]
  60. Xiao, J.; Yin, Y.; Shen, F.; Zhao, J.; Chen, Q. OS005. Treatment with magnesium sulphate reduced the serum level of IL-6in preeclamptic women. Pregnancy Hypertens. 2012, 2, 177. [Google Scholar] [CrossRef]
  61. Elango, T.; Dayalan, H.; Subramanian, S.; Gnanaraj, P.; Malligarjunan, H. Serum interleukin-6 levels in response to methotrexate treatment in psoriatic patients. Clin. Chim. Acta 2012, 413, 1652–1656. [Google Scholar] [CrossRef]
  62. Morton, A.C.; Rothman, A.M.K.; Greenwood, J.P.; Gunn, J.; Chase, A.; Clarke, B.; Hall, A.S.; Fox, K.; Foley, C.; Banya, W.; et al. The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: The MRC-ILA Heart Study. Eur. Heart J. 2015, 36, 377–384. [Google Scholar] [CrossRef] [PubMed]
  63. Ridker, P.M.; Howard, C.P.; Walter, V.; Everett, B.; Libby, P.; Hensen, J.; Thuren, T.; CANTOS Pilot Investigative Group. Effects of Interleukin-1β Inhibition with Canakinumab on Hemoglobin A1c, Lipids, C-Reactive Protein, Interleukin-6, and Fibrinogen. Circulation 2012, 126, 2739–2748. [Google Scholar] [CrossRef] [PubMed]
  64. Ormesher, L.; Higson, S.; Luckie, M.; Roberts, S.A.; Glossop, H.; Trafford, A.; Cottrell, E.; Johnstone, E.D.; Myers, J.E. Postnatal Enalapril to Improve Cardiovascular Function Following Preterm Preeclampsia (PICk-UP). Hypertension 2020, 76, 1828–1837. [Google Scholar] [CrossRef] [PubMed]
Table 1. Postpartum changes of cytokines and angiogenic factors in women with a history of hypertensive disorder of pregnancy compared to the normotensive postpartum controls.
Table 1. Postpartum changes of cytokines and angiogenic factors in women with a history of hypertensive disorder of pregnancy compared to the normotensive postpartum controls.
TNF-αIL-6IL-6/IL-10PlGFsFlt-1sFlt-1/PlGF
6 weeks UC [13]: 89/5
UC [20]: 29/53		UC [20]: 29/53UC [20]
1–3 months UC [21]: 43/50
3 months↑ [22]: 17/16
UC [10]: 22/88		↑ [10,22] ↑ [23]: 23/79UC [23]UC [23]
9 monthsUC [10]↑ [10]
1 year↑ [11]: 31/40UC [11] UC [24]: 48/58↑ [24]↑ [24]
5–8 years UC [25]: 26/15↑ [25]
9–16 yearsUC [26]: 131/56↑ [26]
10 years UC [27]: 16/18UC [27]
11 years UC [12]: 15/16UC [12]
12 years UC [28]: 43/21UC [28]UC [28]
12–22 years ↑ [29]: 249/2241
20 years UC [30]↑ [30]
TNF-α = tumor necrosis factor alpha; IL-6 = interleukin-6; IL-6/IL-10 = interleukin-6/interleukin-10 ratio; PlGF = placental growth factor; sFlt-1 = soluble fms-like tyrosine kinase-1; UC = unchanged; ↑—elevated; numbers in brackets correspond to the article number in the reference list; numbers after the colon represent case patients number/control patients number.
Table 2. Postpartum correlation between angiogenic factors and carotid artery intima-media parameters.
Table 2. Postpartum correlation between angiogenic factors and carotid artery intima-media parameters.
Intima ThicknessIntima: Media
Thickness Ratio
(I/M)		Intima–Media
Thickness (cIMT)
sFlt-1+0.38 [24]: 48 +0.27 [28]: 43
PlGF−0.21 [24]−0.21 [24]−0.25 [28]
sFlt-1/PlGF+0.48 [24]+0.41 [24]
PlGF = placental growth factor; sFlt-1 = soluble fms like tyrosine kinase-1; + = positive correlation with coefficient; − = negative correlation with coefficient; Numbers in brackets correspond to the article number in the reference list; number after the colon represent case patients (if missing—it was not provided in the article).
Table 3. Correlation between angiogenic factors and echocardiography parameters.
Table 3. Correlation between angiogenic factors and echocardiography parameters.
PlGFsFlt-1
Left ventricle posterior wall thickness +0.37 [28]: 43
Global longitudinal strain−0.58 [28]+0.44 [21,43]: 43
End systolic elastance +0.27 [21]
Arterial elastance +0.24 [21]
E/E‘ +0.096 [21]
E/A −0.23 [21]
Aortic root diameter− [14]: 3797
Left atrial diameter− [14]
Left ventricular mass− [14]+0.2 [43]
Left ventricular ejection fraction UC [43]
PlGF = placental growth factor; sFlt-1 = soluble fms like tyrosine kinase-1; UC = unchanged. + = positive correlation with coefficient (if missing—it was not provided in the article); − = negative correlation with coefficient (if missing—it was not provided in the article). Numbers in brackets correspond to the article number in the reference list; number after the colon represent case patients (if missing—it was not provided in the article).
Table 4. Correlation between other CVD risk factors and angiogenic, inflammatory markers.
Table 4. Correlation between other CVD risk factors and angiogenic, inflammatory markers.
PlGFsFlt-1sFlt-1/PlGFIL-6
Systolic blood pressure[14]: 2924
Diastolic blood pressure−0.29 [28]: 43
Mean arterial pressure−0.25 [28]+ [43]: 62
Waist circumference +0.26 [26]: 131
BMI N [43] +0.27 [26]
Triglycerides +0.155 [26]
HDL+0.34 [28]−0.37 [28]−0.31 [28]−0.199 [26]
BMI = body mass index; HDL = high density lipoproteins. + = positive correlation with coefficient (if missing—it was not provided in the article) − = negative correlation with coefficient (if missing—it was not provided in the article). N—no correlation. Numbers in brackets correspond to the article number in the reference list; number after the colon represent case patients (if missing—it was not provided in the article).
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Maselienė, T.; Struckutė, E.; Breivienė, R.; Ramašauskaitė, D.; Dženkevičiūtė, V. The Importance of Inflammatory and Angiogenic Markers in the Evaluation of Early Cardiovascular Disease Risk in Women with Hypertensive Disorders of Pregnancy. J. Cardiovasc. Dev. Dis. 2023, 10, 407. https://doi.org/10.3390/jcdd10100407

AMA Style

Maselienė T, Struckutė E, Breivienė R, Ramašauskaitė D, Dženkevičiūtė V. The Importance of Inflammatory and Angiogenic Markers in the Evaluation of Early Cardiovascular Disease Risk in Women with Hypertensive Disorders of Pregnancy. Journal of Cardiovascular Development and Disease. 2023; 10(10):407. https://doi.org/10.3390/jcdd10100407

Chicago/Turabian Style

Maselienė, Tatjana, Emilija Struckutė, Rūta Breivienė, Diana Ramašauskaitė, and Vilma Dženkevičiūtė. 2023. "The Importance of Inflammatory and Angiogenic Markers in the Evaluation of Early Cardiovascular Disease Risk in Women with Hypertensive Disorders of Pregnancy" Journal of Cardiovascular Development and Disease 10, no. 10: 407. https://doi.org/10.3390/jcdd10100407

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop