Evaluation of Elevated Serum Apelin-13 and D-dimer Concentrations in Individuals Diagnosed with Pulmonary Embolism

doi:10.21203/rs.3.rs-3811286/v1

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Evaluation of Elevated Serum Apelin-13 and D-dimer Concentrations in Individuals Diagnosed with Pulmonary Embolism

https://doi.org/10.21203/rs.3.rs-3811286/v1

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published 02 Apr, 2024

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Background: Given the limited specificity of D-dimer, there is a perceived need to discover a more precise marker for diagnosing individuals who are suspected of having pulmonary embolism (PE). In this study, by Evaluating the increase in the serum level of Apelin-13 and D-dimer, we found valuable findings about Apelin-13, which can be suggested as an auxiliary and non-invasive diagnostic biomarker in individuals with suspected PE, based on the obtained results. Methods: In this case-control study, 52 Iranian individuals with a suspicion of pulmonary embolism, were included and then were separated into two groups based on CT angiography results serving as the gold standard imaging method for diagnosing PE: patients with and without PE. Finally, the serum levels of these markers were compared in these two groups. Results: The mean serum D-dimer levels in patients with PE were significantly elevated (p<0.001) in comparison to those without PE (1102.47 to 456.2 ng/ml). Furthermore, the mean level of Apelin-13 was significantly higher in patients with PE (49.8 to 73.11 ng/L) (p <0.001). The cutoff point of Apelin-13 has been calculated 58.50 ng/ml, with 90.9% sensitivity and 90% specificity. The D-dimer cutoff point was 500 ng/ml, with 95.5% sensitivity and 43.3% specificity. Conclusions: Based on the results of this study, the serum level of Apelin-13 can be used as novel diagnostic and screening biomarker in patients with pulmonary thromboembolism Keywords: Pulmonary embolism, Thromboembolism, Apelin-13, D-dimer.

Pulmonary thromboembolism, commonly known as pulmonary embolism (PE), is a clinical and pathophysiological syndrome arising from the obstruction of a pulmonary artery or its branches by emboli originating from the venous system or right heart. This obstruction leads to dysfunction in the pulmonary circulation and respiratory system (1, 2). Pulmonary embolism (PE) stands as the third most prevalent cardiovascular condition, following coronary artery disease and stroke (3). Additionally, over the past two decades, there has been a consistent rise in the occurrence of PE (4–8). Individuals diagnosed with PE and categorized as high-risk encountered a mortality rate of 25% (9), Even in cases of stable PE patients, the mortality rate was recorded at 0.7% (10). Diagnosing PE is challenging due to the presence of nonspecific signs, symptoms, and associated risk factors (11, 12).

The gold standard for identifying the occurrence of an acute PE is through computed tomography pulmonary angiography (CTPA). This method, known for its sensitivity and specificity, not only confirms the existence of a PE but also evaluates the extent and severity of the anatomical clot burden. The decision to employ contrast and undergo radiation exposure in the assessment of a potential PE is a common dilemma in emergency medicine. The legitimate concern lies in the radiation load, and it's worth noting that CTPA is not recommended for individuals in the low-risk category, especially those with a negative D-dimer result (13).

The D-dimer is a product formed during the coagulation and breakdown of blood clots, and its levels can be determined by analyzing a blood sample. The release of D-dimer occurs as a result of the breakdown of a blood clot (14–16). D-dimer is formed through the degradation of cross-linked fibrin, and in patients suspected of having PE, the levels of D-dimer in the blood provide an indication of the likelihood of experiencing PE (17, 18). Highly sensitive plasma D-dimer tests, employing enzyme-linked immunosorbent assays to quantify this fibrin degradation product, can reliably rule out PE in individuals with a low or intermediate pretest probability of PE. On the other hand, older latex or erythrocyte agglutination assays are restricted to excluding PE solely in patients with a low pretest probability (19, 20).

Apelin also referred to as APLN, a novel discovered naturally occurring multifunctional peptide ligand, interacts with APJ, a G protein-coupled receptor. The genes responsible for apelin and APJ exhibit broad expression in diverse bodily tissues, and the structure of apelin remains remarkably preserved across various species (21, 22). Apelin serves as the innate ligand for APJ and its sequence of amino acids closely resembles that of the angiotensin (Ang) II receptor type-1 receptor (AT1R) and the impact of preproapelin, a precursor composed of 77 amino acids, involves enzymatic cleavage and processing, resulting in various molecular forms across different tissues. Shorter variants, like Apelin-13, demonstrate heightened efficacy compared to their longer counterparts (23) which show the highest level of activity at the receptors (24), and its specific binding region for the APJ receptor is located at its C-terminal (22). The apelin-APJ system has been identified as a contributing factor to the development of several prevalent conditions, including heart failure, hypertension, atherosclerosis, type 2 diabetes mellitus, and ulcerative colitis(25). Apelin demonstrates a dual-phase influence on vasomotion and its vasodilatory effect is dependent on the endothelium. When apelin acts directly on the smooth muscle cells of arteries and veins without endothelium, it elicits a vasoconstrictive response (26, 27). Notably, individuals with acute respiratory distress syndrome (ARDS) display a substantial increase in Apelin levels, observed in both lung tissue and plasma (28). On the contrary, individuals diagnosed with pulmonary arterial hypertension (PAH) demonstrate a decrease in Apelin levels (29). Hemodialysis patients with PAH experience notably lower serum apelin levels compared to those with normal arterial pressure, and this disparity remains unaffected by hemodialysis (30). It's worth noting that approximately one-third of patients experiencing symptoms of venous thromboembolism (VTE) are identified with PE, while the remaining two-thirds receive a diagnosis of isolated deep vein thrombosis (DVT)(31) D-dimer shows a lack of precision in identifying VTE, particularly in elderly patients with notable coexisting conditions including infection, syncope, heart failure, trauma, and malignancies (32).

These findings suggest the participation of the apelin/APJ pathway in the onset of respiratory conditions and due to the diagnostic uncertainty associated with D-dimer, we conducted this Case-Control study to assess the increase in Serum Apelin-13 and D-dimer Levels among patients experiencing PE within the Iranian population.

Study design

This study was conducted as a case-control study to investigate serum levels of Apelin-13 and D-dimer in 52 inpatients suspected of PE within 6 months at Rouhani hospital, in Babol, Iran, from September 2018 to April 2019. Patients based on symptoms suggestive of PE were eligible to be included in this study. Patients were excluded if they had malignant diseases, Recurrence of PE, patients who received drugs that affect on the level of D-dimer and Apelin-13; such as long-term use of warfarin and other anticoagulant drugs that have a negative effect on increasing the level of D-dimer, having history of PE. The ethics committee of Babol University of Medical Sciences approved the study with the number IR.MUBABOL.HRI.REC.1397.272. A written informed consent was obtained from all the patients to participate in this trial.

Study procedure

The study included 52 individuals with potential diagnoses of PE based on their clinical symptoms, as determined by the Wells score. The Wells score is a clinical prediction tool employed to categorize patients suspected of having PE. Physicians utilized the seven-item Wells score, which ranges from 0 to 12.5 (higher scores indicating an increased probability of pulmonary embolism), to assess the patient's clinical pretest probability (C-PTP). A Wells score of 0 to 4.0 was categorized as low C-PTP, 4.5 to 6.0 as moderate C-PTP, and 6.5 or higher as high C-PTP. All the Individuals exhibiting a high clinical pretest probability (C-PTP) underwent chest imaging (CT angiography of pulmonary). Patients with chest imaging finding suggestive of PE received anticoagulant therapy; otherwise, anticoagulant therapy was not performed for other patients. In all the inpatients, venous blood samples were collected within the initial 6 hours of admission and before beginning anticoagulation to check the serum levels of Apelin-13 and D-dimer. In this case-control study, based on CT angiography findings, as a diagnostic gold standard, 52 Participants were segregated into two groups based on the presence or absence of PE. At the end, the serum levels of these markers were compared in two groups.

CTPA Assessment

All CTPA examinations were carried out in a 64-slice CT scanner. In adherence to the standard CTPA protocol, an intravenous contrast agent of 80–100 mL, with an iodine concentration of 350 mg/mL, was administered to all patients. Two senior radiologists investigated all CTPA images. The examination reported the existence of any intraluminal filling defect, along with its location characterized by central or peripheral, and unilateral or bilateral distribution within the pulmonary arterial system and its branches down to a sub-segmental level. Central pulmonary embolism (PE) was defined as the presence of an embolus within the right or left main pulmonary artery. Lobar PE was identified when an embolus was present in the right or left lobar pulmonary arteries. Peripheral PE was described as the presence of an embolus in the segmental and sub-segmental arteries.

Serum Apelin-13 Concentrations Determination by ELISA

In order to check the markers, 3–5 ml of blood sample was taken from each patient. The amount of D-dimer and Aplin-13 by ELISA (Enzyme-Linked Immunosorbent Assay) was measured. Due to measure Apelin-13, serum was separated from the blood cells using centrifugation for 10 minutes at 5000g and kept frozen at -80°C till the analysis was performed. The amount of Apelin-13 was detected using ELISA kit. The kit is available from Eastbiopharm under catalog number CK-E11153. The sensitivity of this method is 0.27 ng/L and this method is quantitative (Assay range of 0.5 to 200 ng/ml). Assays were carried out according to the kit instructions.

Statistical analysis

Sample size was calculated as all patients according to their symptoms who had a possible diagnosis of PE, they were included in the study during the 6 months, based on the inclusion and exclusion criteria. The analysis of the data was conducted utilizing The Statistical Package of Social Science Software (SPSS version 18). The variables with normal distribution were reported as percentages, mean values and standard deviation. Variables without normal distribution were reported as median with range. Chi-square test and t-test were utilized for comparison of proportions. The Mann-Whitney test was utilized for non-normally distributed variables to compare between the two groups. Receiver Operating Characteristic (ROC) analysis was employed to establish cutoff points and examine the sensitivity and specificity. The overall ROC curve performance was quantified using computing AUC (area under the curve). A p-value less than 0.05 was deemed statistically significant in all comparisons.

In this study, sampling was available and 52 inpatients in Rohani hospital in Babol during the period of 6 months with symptoms suspected to PE, they included in this study. Based on the CT angiography finding as the diagnostic gold standard, 22 patients (42.3%) were with PE and 30 patients (57.7%) were without PE. Of these, 23 (44.2%) men and 29 (55.8%) women entered in this study. The mean age of the patients was 63.67 ± 10.00 years, ranging from 46 to 86 years. In the examination of the D-dimer marker without taking embolism into account in the surveyed individuals, 14 patients (26.9%) had a normal D-dimer and 38 patients (73.1%) had increased D-dimer level. In the investigation of Apelin-13 marker without considering embolism in the studied patients, based on the calculated cutoff point, 29 patients (55.8%) had the Apelin-13 level below the cutoff point and 23 patients (44.2%) had the Apelin-13 level were above the cut-off point. The average level of D-dimer in all patients was equal to 729.85 ± 90.471 ng/ml (minimum 107 and maximum 2150) and the average level of Apelin-13 was equal to 59.50 ± 15.15 ng/ml (minimum 28 and maximum 94). The age and gender variables showed no significant difference between patients with pulmonary embolism and those without it (p = 0.34 and p = 0.68, respectively). On the other hand, among the 52 patients suspected of PE who were investigated, 22 participants (42.3%) had PE and patients in the without PE group including 13 patients (25.0%) had aggravated COPD, 9 patients (17.3%) had pulmonary edema, 5 patients (9.6%) had aggravated asthma, and 3 people (5.8%) had angina. The average D-dimer level in patients with pulmonary embolism (PE) (1102.47 ± 55.16) was significantly higher than in those without PE (456.20 ± 53.36), and this difference was found to be statistically significant (p < 0.001). Additionally, the mean Apelin-13 level was significantly elevated in the PE group compared to the non-PE group (73.11 vs. 49.8 ng/ml, p < 0.001). According to the ROC curve analysis, the Apelin-13 cut-off point was determined to be 50.58 ng/ml, with a reported sensitivity of 90.9% and specificity of 90% (Fig. 1).

Among the 22 patients with PE, 20 patients (90.9%) had Apelin-13 levels more than 58.50 ng/ml which was significant (p < 0.001). Based on the available references, the D-dimer cutoff point is considered equal to 500 ng/ml, and based on this cutoff point, the sensitivity is 95% with a confidence interval of 87–100% and the specificity of 43% with a confidence interval of 26–61% was reported. A D-dimer level exceeding 500 ng/ml was observed in 21 patients (95.5%) within PE group with p = 0.002 which conclude the relationship was significant. In evaluation of relationship between Apelin-13 level and having PE according to Table 2–3, it can be stated that in 20 patients (90.9%) with PE, the level of Apelin-13 has increased which the difference was reported significant (p < 0.001). Table 1 shows that in either woman and men patients, the average D-dimer level in individuals with PE was significantly higher than that in others without it and the difference reached statistical significance (p = 0.001 and p = 0.001, respectively). Both in women and men, the mean Apelin-13 level was significantly higher in individuals with PE compared to those without it, with statistical significance observed (p < 0.001).

Table 1

; Quantitative comparison of D-dimer and apelin-13 levels in patients in two groups by gender
	Gender	PE group (mean ± SD)	non-PE group (mean ± SD)	P value
D-dimer (ng/ml)	Male	1379.526 ± 67.76	558.172 ± 86.25	0.001
D-dimer (ng/ml)	Female	910.343 ± 69.01	367.199 ± 00.76	0.001
Apelin-13 (ng/ml)	Male	75.14 ± 11.19	50.5 ± 36.94	< 0.001
Apelin-13 (ng/ml)	Female	71.8 ± 85.82	48.9 ± 69.98	< 0.001

Table 2 shows that in both individuals aged below 60 and those aged 61 years or older, the mean level of D-dimer in patients with PE is notably elevated compared to patients without PE, and this disparity is significant (p = 0.002 and p < 0.001, respectively). In both age groups—those under 60 years old and those aged 61 years or older—patients with PE exhibited a significantly higher average level of Apelin-13 compared to those without it, with significant differences (p < 0.001). Among the male patients with PE, 88.9% showed a significant increase in Apelin-13 levels (p < 0.001), while in female patients with PE, 84.6% exhibited a significant elevation in Apelin-13 levels (p < 0.001). Based on the results of Table 3 shows that 20 patients with PE (90.9%) had serum level of D-dimer and Aplin-13 were reported positive. However, the relationship between these two markers in patients with PE was not significant (p = 0.09). 17 patients without PE had high D-dimer (56.7% false positive and 43.3% of specificity) and 3 patients without PE had high Apelin-13 (10% false positive and specificity of 90%). In patients without PE, 13 patients (43%) both D-dimer and Apelin-13 levels was negative and this relationship was not statistically significant (p = 0.23). Among individuals with PE, 21 of them had a high D-dimer level (95.5% diagnostic sensitivity) and 20 patients had a high Apelin-13 level (90.9% diagnostic sensitivity).

Table 2

; Quantitative comparison of D-dimer and apelin-13 levels in patients in two groups by age group
	Age	PE group (mean ± SD)	No PE groups (mean ± SD)	P value
D-dimer (ng/ml)	≤ 60	715.143 ± 17.82	367.177 ± 33.38	0.002
D-dimer (ng/ml)	≥ 61	1247.48 ± 81.27	516.210 ± 00.58	< 0.001
Apelin-13 (ng/ml)	≤ 60	71.12 ± 83.60	50.6 ± 42.21	< 0.001
Apelin-13 (ng/ml)	≥ 61	73.10 ± 69.92	48.9 ± 83.49	< 0.001

According to Table 3, the positive predictive values of Apelin-13 and D-dimer were 86.9% and 55.2%, respectively. Furthermore, Apelin-13 and D-dimer demonstrated negative predictive values such as 93.1% and 92.8%, respectively.

Table 3

; Comparison of patients in case-control groups based on the cutoff points of Apelin-13 and D-dimer
Groups	Apelin-13	D-dimer		P value
		Positive (n)	Negative (n)
Without PE	Positive (n)	3	-	0.23
	Negative (n)	14	13
PE	Positive (n)	20	-	0.09
	Negative (n)	1	1

This research is among a limited number of studies that have explored the serum concentration of Apelin-13 in individuals with presumed PE. Only a handful of sporadic studies have been conducted to examine the serum concentration of Apelin-13 in PE. Over the past few years, there has been a growing body of scientific studies delving into the role of Apelin-13 in the pathophysiology of hypoxic conditions (33, 34). While the impact of hypoxia on the regulation of Apelin-13 in hypoxic conditions in humans should be clarified, several studies have demonstrated that the expression of Apelin-13 in endothelium, adipocytes and lung cells of animal samples was enhanced under hypoxic conditions (33, 35, 36).

During the acute phase of pulmonary embolism (PE), numerous vasoactive substances are released, and Apelin-13 might exert an antagonistic influence on vasoconstrictor mechanisms that rely on nitric oxide (NO) (37, 38).

According to several studies, the current D-dimer biomarker, which is used to diagnose acute PE in suspected patients, does not have high specificity. In low-risk populations, the sensitivity of D-dimers is high, but their specificity for detecting deep vein thrombosis (DVT) or PE is diminished (39).

In this research, it was found that the level of these two factors increases dramatically Among individuals experiencing PE. In another investigation related to the Apelin-13 biomarker, the study conducted by Selimoglu et al. is noteworthy. Their research indicated a notable elevation in the mean serum Apelin-13 level within the PE group compared to the control group. This aligns with the outcomes observed in the current study (40). In another study conducted by Sen et al., it was concluded that the level of Apelin-13 increases among individuals diagnosed with PE (40). The results suggest that Apelin-13 could be viewed as a novel biomarker and a potential focus for therapy in future cases of acute PE.

There is a consensus regarding the increase in D-dimer serum level with venous thromboembolism, and many studies in this field reported similar results (41). According to Yoshiiwa et al., examining D-dimer levels proves beneficial for promptly diagnosing thromboembolism. They further highlighted that an elevated D-dimer level is considered a contributing factor for PE (42). Tang et al. observed that a rise in D-dimer levels correlated with an elevated likelihood of pulmonary thromboembolism (43). A notable outcome from the current study was the demonstrated high sensitivity and specificity of Apelin-13 at the threshold of 58/50 ng/ml.

The 90.9% sensitivity of this marker means that out of every 100 people who have PE according to the gold standard, based on the level of Apelin-13 higher than 58.5 ng/ml, it has correctly diagnosed more than 90 people, which It has high sensitivity. Regarding the 90% specificity of this marker, it can be said that out of 100 people who were healthy according to the gold standard, the level of Apelin-13 above 58.5 ng/ml correctly identified 90 people as healthy people, which is much higher than the findings related to D-dimer are in the studies.

Karataş et al. determined a cutoff point of 1579 ng/ml for Apelin-13 in their study, revealing a sensitivity of 92.7% and a specificity of 96.7%. The difference in the obtained cut point is due to the difference in the Apelin-13 measurement kit (44). Also, the sensitivity and specificity obtained in the Karataş study is slightly higher than the present study. But in both studies, the demonstrated sensitivity and specificity at this level suggest that the serum Apelin-13 level can serve as a novel diagnostic biomarker for individuals with pulmonary thromboembolism.

Makris et al reprted that the most specific test to confirm the definitive diagnosis of pulmonary thromboembolism is selective pulmonary angiography, which can also detect emboli as small as 1–2 mm, but this method is invasive and causes possible complications in the patient (45).

Also, although CT angiography has recently been proposed as a diagnostic gold standard in studies (46), but in people who have a low susceptibility based on the existing criteria and scores for diagnosis, performing this method is not justified. Therefore, according to the finding of high sensitivity and specificity for Apelin-13 as a less expensive, non-invasive and uncomplicated diagnostic biomarker, it can be suggested to identify people with pulmonary thromboembolism.

The lung serves as the primary origin of Apelin-13 receptors in the bloodstream (47), Therefore, the application of this marker in identifying lung diseases, notably pulmonary thromboembolism, facilitates early diagnosis and, consequently, the timely initiation of patient treatment.

The sensitivity and specificity of D-dimer constitute another aspect of debate within this research at its standard cut point of 500 ng/ml. In the current study, the sensitivity is 95% and the specificity is 43%. At the conventional threshold, Gao et al. documented D-dimer's sensitivity and specificity as 96.2% and 50%, respectively(48).

With its elevated sensitivity, D-dimer can serve as an effective screening method (39). Glober et al. observed a sensitivity of 95.7% and a specificity of 40% for D-dimer in diagnosing PE in their study (49).

In a review study the sensitivity and negative predictive value of D-dimer by ELISA for PE were both 100% (50). Our study exhibited a greater sensitivity compared to the review study, whereas the negative predictive value was inferior to that particular investigation.

In the context of our study, the negative predictive values for Apelin-13 and D-dimer tests in PE were found to be 93.1% and 92.8%, respectively.

Considering that the negative predictive value shows how likely it is that the person is really healthy if the desired test is negative, then this index helps us to use these factors for quick and low-cost triage among individuals with suspected PE, and in high serum levels, standard imaging methods were used.

In our research, Apelin-13 and D-dimer tests demonstrated positive predictive values of 86.9% and 55.2%, respectively, for PE. Considering that the positive predictive value shows how likely it is that the person is really sick if the desired test is positive, then this index helps us to make the right decision to choose the diagnostic algorithm, and Apelin-13 can be helpful in rejecting many false positive cases of the testing of D-dimer.

It is necessary to explain that the difference in the sensitivity and characteristics of the biomarkers of the present study can rely on diverse factors such as the type of kit used, the type of measuring device, laboratory factors and the time of measurement of these factors in individuals according to both the disease's acute and chronic stages or before the onset of the disease.

Of course, due to the lack of studies during the disease and the measurement of these factors in the acute phase and before the start of anticoagulants, it can be claimed that this research is one of the first studies conducted in this field.

In a review study, Pulivarthi et al., considering the cut-off point of 500 and differences in sensitivity and specificity in different studies, stated that Several elements contribute to the variability in sensitivity and specificity of the D-dimer test. These factors encompass the extent of thrombosis and fibrinolytic activity, duration of symptoms, anticoagulant treatment, concurrent surgical or medical conditions, inflammatory diseases, advanced age, pregnancy, postpartum period, history of previous venous thromboembolism (VTE), and the presence of malignancy(51).

An important discovery in this study, recognized as a strength, involves the assessment of two biomarkers—D-dimer and Apelin-13—across various age groups and in both male and female populations. In patients experiencing embolism, both biomarkers exhibited a substantial increase in levels for individuals under 60 years and those over 60, a trend observed across both genders.

In this research, it was found that the level of these two factors increases dramatically in individuals with PE. Derived from the findings of the current investigation, the serum concentration of Apelin-13 emerges as a novel biomarker suitable for diagnosing and screening individuals with pulmonary embolism.

Ethical Approval: This study was approved by the ethics committee of Babol University of Medical Sciences approved the study with the number IR.MUBABOL.HRI.REC.1397.272. This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
Consent to participate: returned informed consent was taken from the participants of this study. All participants participated in the study knowingly and with consent.
Consent for publication: Written informed consent was obtained from the patient for publication of this study and accompanying images.
Conflict of interest: None
Funding: None
Availability of data: data is available upon request from corresponding authors.
Acknowledgments: The authors would like to thank the researchers whose work is included in this study.
Author Contribution: "Alireza Mehrban and Mahmoud Monadi conceived of the presented idea, developed the theory and performed the computations. Karim Hajian Taliki collected the data and performed the statistical analysis of the data. Alireza Mehrban, Fatemeh Ahmadi Hajikolaei, Mehdi Karimi, Reza Khademi, and Akram Ansari wrote the main manuscript. Durdi Qujeq and Mahmoud Monadi helped supervise the project. All authors provided critical feedback and helped shape the research, discussed the results and contributed to the final manuscript."

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Evaluation of Elevated Serum Apelin-13 and D-dimer Concentrations in Individuals Diagnosed with Pulmonary Embolism

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Introduction

Material and Methods

Study design

Study procedure

CTPA Assessment

Serum Apelin-13 Concentrations Determination by ELISA

Statistical analysis

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