Pre-eclampsia Paradigm: Analyzing Angiogenic Markers, Cardiac Biomarkers, and Maternal Myocardial Indices

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INTRODUCTION

The incidence of pre-eclampsia (PE) is 3–8%. In low-resource settings, approximately 16% of maternal mortality occurs due to hypertensive disorders of pregnancy.^[1] The complications of PE are HELLP syndrome, maternal eclampsia, and long-term cardiovascular disease. Fetal risks include preterm delivery, fetal growth restriction (FGR), and stillbirth due to placental insufficiency.^[2] Early detection of women at risk can prevent cardiovascular and other complications.^[1,2]

The underlying pathophysiology of PE is abnormal placentation, endothelial dysfunction, and imbalance among angiogenic factors, namely placental growth factor, along with anti-angiogenic factors, mainly soluble fms-like tyrosine kinase-1.^[3] The angiogenic imbalance leads to diastolic dysfunction and cardiovascular diseases.^[4] N-terminal pro-brain natriuretic peptide (NT-proBNP) levels are an early predictor of cardiovascular health since it increases with increased cardiac stress.^[5] Myocardial work indices (global work index [GWI], global constructive work [GCW], global wasted work [GWW], global work efficiency [GWE]) are an indicator of left ventricular performance. They have been shown to detect early alterations in cardiac mechanics in PE, complementing both angiogenic and natriuretic biomarkers.^[3-6]

Integrating biomarkers such as NT-proBNP, soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PLGF) ratio, with advanced echocardiographic measures like myocardial work can predict risk stratification and contribute to better maternal and fetal outcomes.^[3-6]

This is a pilot study to integrate angiogenic markers, natriuretic peptides, and myocardial work indices as a combined diagnostic framework in predicting cardiovascular disease in PE.

MATERIALS AND METHODS

The Department of Obstetrics and Gynecology conducted a prospective study in Dayanand Medical College and Hospital. Approval for the study was obtained from hospital’s “Ethical committee” with Ref.no. (IEC/2025/1018).

The inclusion criteria were all antenatal women between 20 and 37 weeks of gestation singleton live intrauterine pregnancy. The exclusion criteria are intrauterine fetal demise, fetal congenital anomaly, multiple pregnancy, <20 weeks, >37weeks period of gestation, any other medical co-morbidity, including chronic hypertension.

A total of 120 antenatal women from 20 to 37 weeks were recruited from May 1, 2025, to July 31, 2025. The patients were categorized into two groups: group A (60 women with PE) and group B (60 normotensive women).

A comprehensive clinical evaluation was undertaken for each patient, including assessment of maternal age, obstetric history, and relevant risk factors. Obstetric and general physical examination was performed. Routine antenatal investigations, angiogenic markers (sFlt/PLGF ratio), biochemical cardiac markers (NT-proBNP), and echocardiography were done for all participants.

An ECLIA on a cobas analyzer (Roche Diagnostics) assessed serum “PLGF” and “sFlt-1” (pg/mL). Established thresholds indicate a normal sFlt-1/PlGF ratio as ≤38, whereas ≥85 indicates PE. In our investigation, a raised sFlt-1/PLGF ratio >102 was considered abnormal (derived from receiver operating characteristic [ROC] curve analysis).^[7] Serum levels of NT-proBNP (pg/mL) were assessed with ECLIA assays on the cobas platform (Roche Diagnostics).^[8] A cut-off value >300 pg/mL based on ROC curve analysis was used to indicate myocardial stress. Myocardial work indices were evaluated through speckle-tracking echocardiography, and thresholds were evaluated by ROC analysis. The indices such as global work index <1901 mmHg%, global constructive work <2250 mmHg%, global wasted work >176 mmHg%, and global work efficiency <94.1% have been assessed.^[6] Antenatal care was provided in accordance with standard operating procedures. Fetal and maternal outcomes were followed up until delivery.^[6-8]

RESULTS

A total of 120 pregnant women were recruited; 60 women with PE constituted Group A, and 60 normotensive women comprised Group B. Baseline demographic characteristics were comparable regarding maternal age, thyroid status, and diabetes status. Primigravidity was observed with significantly greater frequency in Group B (P = 0.025). Women with PE had significantly greater systolic and diastolic blood pressures (P < 0.001). NT-proBNP concentrations, the spot protein–creatinine ratio, and angiogenic markers like sFlt-1/PLGF ratio were significantly higher in Group A [Table 1].

Echocardiographic evaluation demonstrated significant left ventricular remodeling in increased “left ventricular mass index and left atrial volume index in group A. Diastolic dysfunction was evident with increased A-wave velocity, reduced E-wave velocity, and elevated E/e' ratio, while left ventricular ejection fraction” remained preserved. The global longitudinal strain (GLS) analysis revealed a statistically significant difference between the study groups [Table 2].

A statistically significant difference in myocardial parameters, GWI, GCW, GWW, and GWE was observed between two groups (P = 0.001) [Table 2].

The sFlt-1/PLGF ratio can be used to predict interval to delivery, which has been recorded [Table 3]. Women with higher sFlt-1/PLGF ratios (>150) delivered within 2–4 weeks of assessment, compared with those with ratios between 38 and 150 (P = 0.080).

The ROC-derived cut-off values revealed the highest sensitivity and specificity of GWW >176 mmHg% and a GWE under 94.1%, respectively. NT-proBNP levels exceeding 300 pg/mL demonstrated high sensitivity, while a sFlt-1/PLGF ratio >102 showed high specificity in identifying PE [Table 4].

The diagnostic performance of myocardial work indices, angiogenic markers, and NT-proBNP done with area under the curve (AUC) values (0.90–1.00) [Figure 1]. Among the myocardial work parameters, both GWW and GWI demonstrated the highest diagnostic accuracy.

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Figure 1:

Receiver operating characteristic (ROC) curve analysis of myocardial work indices, angiogenic markers, and cardiac biomarkers. (GLS: Global longitudinal strain, GWI: Global work index, GCW: Global constructive work, GWW: Global wasted work, GWE: Global work efficiency, sFLT/PLGF: Soluble fms like tyrosine kinase, PlGF: Placental like growth factor, NT-proBNP: N-Terminal pro-B-type natriuretic peptide).

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Scatter plot analysis revealed a statistically significant correlation among sFlt-1/PLGF ratio and GWE. Higher sFlt-1/PLGF ratios have been associated with a progressive decrease in GWE [Figure 2].

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Figure 2:

Correlation of myocardial work and cardiac biomarkers with angiogenic markers. GWW: Global wasted work, GCW: Global constructive work, (GWW: Global waste work, GWE: Global work efficiency, NT-proBNP: N-Terminal pro-B type natriuretic peptide).

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Adverse maternal outcomes such as severe PE, ICU admission, and peripartum cardiac complications were more frequent in group A [Figure 3]. Neonatal outcomes such as Apgar scores, preterm delivery, low birth weight, and neonatal intensive care unit admission were significantly increased in the PE group [Figure 4].

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Figure 3:

Maternal morbidity and critical care requirements across study groups. (PPCM: Postpartum cardiomayopathy).

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Figure 4:

Comparison of neonatal and fetal outcomes between the two study groups. (OLIGO: Oligohydramnios, NICU: Neonatal intensive care unit).

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DISCUSSION

Angiogenic markers, cardiac biomarkers, and myocardial work were analyzed to predict cardiovascular impact in PE. The sFlt-1/PLGF ratio significantly increased in placental hypoxia and endothelial dysfunction.^[3] The ISSHP 2021 guidelines highlight that sFlt-1/PLGF ratio <38 effectively rules out PE, while higher values predict the development of PE within 1–4 weeks.^[9] This ratio also aids in monitoring disease progression and predicting adverse outcomes, notably FGR, preterm birth, and stillbirth. Research by Giorgione et al. observed that elevated sFlt-1/PLGF ratios are correlated with cardiac remodeling in hypertensive pregnancies.^[3,9,10]

In our study, NT-proBNP levels were statistically significantly greater in women having PE in comparison to normotensive pregnant women, reflecting increased myocardial stress. NT-proBNP is elevated in response to ventricular stretch, and causing greater risk of maternal cardiovascular disease.^[5] Zeng et al. also observed that NT-proBNP is a useful biomarker for diagnosing and evaluating cardiac involvement in pre-eclamptic women.^[5]

Our research demonstrated that PE women had higher left ventricular filling pressures (P = 0.001). The E/e' ratio is a validated marker of diastolic function, and higher values reflect impaired relaxation and elevated filling pressures. These findings are consistent with a systematic review as well as meta-analysis by the American Heart Association, which also reported similar findings.^[4] A statistically significant increase of left ventricular mass index (LVMI) and relative wall thickness (RWT) (P = 0.001) was observed. These changes suggest a compensatory remodeling response for maintaining left ventricular performance under increased cardiac workload. Underscored a strong positive correlation between BNP levels, LVMI, and RWT in women having PE.^[4] GLS represents the longitudinal deformation of the myocardium and provides additional insights into systolic function. Although it was not a predefined primary endpoint of this study, the changes observed in GLS might suggest early functional alterations in the myocardium among the study participants.

Myocardial work indices, such as “global constructive work,” “global wasted work,” and “global work index,” have been significantly greater in PE women in current research (P = 0.001), suggesting significant alterations in cardiac mechanics. Piao et al. reported similar increases in myocardial work parameters among pre-eclamptic women, supporting their relevance in identifying subclinical myocardial dysfunction.^[6] The observed rise in GWI and GCW reflects myocardial contractile effort required to compensate for increased afterload, while elevated GWW suggests greater myocardial wall stress and reduced mechanical efficiency. These parameters can be beneficial in predicting cardiovascular diseases.^[6,11]

ROC analysis demonstrated a statistically significant inverse correlation of GWE with sFlt-1/PLGF ratio (r = −0.275, P = 0.034). This indicates that progressive angiogenic dysregulation is accompanied by a gradual decline in myocardial work efficiency. Unlike absolute myocardial work indices that primarily reflect compensatory increases in workload, GWE incorporates both constructive and wasted myocardial work, thereby providing an integrated measure of overall cardiac efficiency. The worsening placental dysfunction parallels escalating maternal cardiovascular stress, even when left ventricular ejection fraction remains preserved. Current finding supports the role of GWE as a marker of disease severity.^[3]

In our study, myocardial work indices effectively differentiated PE from normotensive pregnancy, with global wasted work demonstrating optimal diagnostic accuracy (AUC = 1.00) in detecting early myocardial involvement despite preserved ejection fraction. NT-proBNP as well as sFlt-1/PLGF ratio demonstrated strong diagnostic performance, indicating angiogenic imbalance and myocardial stress in PE, respectively.^[3,5,6,12]

In women having PE, sFlt-1/PLGF ratio appears to be useful marker for forecasting the need for an earlier delivery. In the present study, higher sFlt-1/PLGF ratios were associated with significantly shorter intervals to delivery, with a median delivery interval of approximately four weeks. This relationship likely reflects progressive angiogenic imbalance resulting from worsening placental ischemia, leading to widespread maternal endothelial dysfunction. Dröge et al., similarly described that increased sFlt-1/PLGF ratio reliably predicts delivery within a four-week window in women with PE.^[3,9,13]

Overall sFlt-1/PLGF ratio, NT-proBNP, and myocardial work indices (GWI, GWW, GCW) were all significantly elevated with PE. GWE was significantly decreased in PE. All these findings were associated with adverse maternal and neonatal outcomes.

CONCLUSION

The current research highlights that women with PE display significant angiogenic imbalance, increased NT-proBNP levels, and impaired myocardial work. These abnormalities were closely related to adverse maternal and fetal outcomes. The relevance of integrating angiogenic markers, cardiac biomarkers, and myocardial work indices can predict subclinical cardiovascular involvement.

To the best of our knowledge, our study seems to be the pilot study to integrate angiogenic markers, cardiac biochemical, and myocardial work in PE; more extensive research is required for validation of these results.