In this study, we observed that high-risk PE patients had significantly higher mean PAP, PAOI, and YKL-40 levels than other patients and healthy controls. In addition, in the comparison of the high-intermediate-risk group, whose thrombolytic treatment plan is decided according to follow-up, and the high-risk group, who receive early thrombolytic therapy, we observed that the high-risk group had significantly higher YKL-40 levels at diagnosis. Evaluation of the sensitivity and specificity of troponin-I and YKL-40 levels in the differentiation of high-risk and high-intermediate-risk patients showed that troponin-I was more sensitive while YKL-40 level had higher specificity. In addition, YKL-40 was more strongly correlated with mean PAP than troponin-I.
The classification of PE is based on clinical presentation as massive (high-risk), submassive (intermediate-risk), and nonmassive (low-risk) 10, 11. Transthoracic ECHO is the gold standard method for assessing right ventricular dysfunction in acute submassive PE using parameters such as dilation of the right ventricle, hypokinesis of the right ventricular wall, paradoxical movement of the interventricular septum, tricuspid regurgitation, pulmonary artery dilation, and increased right-to-left ventricular end-diastolic diameter ratio 12, 13.
Cardiac troponin-T and troponin-I are cardiac muscle-specific enzymes. In acute right heart failure associated with massive PE, dilation of the right ventricle increases its oxygen demand. Assessment of troponin, BNP, and NT-proBNP may be useful as a prognostic evaluation to distinguish high- and intermediate-risk patients from low-risk patients, and can also be used to further stratify patients at intermediate risk into low-intermediate and high-intermediate risk groups. However, elevation of these markers may also be associated with conditions such as congestive heart failure, acute exacerbation of chronic obstructive pulmonary disease, acute kidney disease, sepsis, trauma, and rhabdomyolysis 1, 14. Although cardiac biomarkers have an important place in clinical risk scoring, there is no definitive cut-off value to differentiate high-risk and high-intermediate-risk patients. Consequently, the decision to initiate thrombolytic therapy requires clinical observation in the high-intermediate-risk group. However, delaying treatment for clinical observation puts the patient at risk of sudden death due to hypoxic respiratory failure and hemodynamic collapse. Therefore, alternative biomarkers are needed for clinical scoring.
YKL-40 is an inflammatory biomarker produced by macrophages in atherosclerotic lesions, as well as by endothelial and vascular smooth muscle cells and possibly even activated hepatic stellate cells in a late stage of differentiation 15. YKL-40 also plays an important role in the regulation of VEGF synthesis. For this reason, significant increases in YKL-40 have been observed in diseases associated with angiogenesis, inflammation, extracellular remodeling, and fibrosis 16, 17. YKL-40 levels were also found to be significantly elevated in individuals with cardiovascular and liver disease compared to the healthy population 15, 16, 18. Moreover, patients with high plasma YKL-40 levels were found to be twice as susceptible to ischemic stroke and VTE 9, 19. Previous studies on PE have also shown that VEGF-D level increases in correlation with clinical risk score and emphasized that this parameter may guide early fibrinolytic treatment 4. The present study on YKL-40, which is involved in VEGF synthesis, was planned in the same direction.
Our results indicate that high-risk and high-intermediate-risk PE was more frequent in patients with low ejection fraction. This may be because patients with low ejection fraction have greater coagulopathic tendency or because immobilization is more likely in these patient groups. In addition, we observed that PAOI increased between the patient groups in correlation with their PE clinical score. Troponin-I is an important marker of right heart dilation and cardiac dysfunction, and its elevation in intermediate- and high-risk patients may be related to thrombus burden. In contrast, YKL-40 level was found to be lower in patients with high-intermediate-risk PE, for whom the decision to initiate thrombolytic therapy was based on hemodynamic instability during follow-up, compared to patients with high-risk PE. YKL-40 was also positively correlated with PAOI, troponin-I level, and mean PAP. Evaluated in the context of previous studies, these findings suggest that YKL-40 may be a biomarker indicating both increased thrombotic tendency and thrombus load. YKL-40, which also plays an important role in neovascularization, may be elevated due to the increased need for vascularization in response to cardiac dilation. In the ROC curve analysis, YKL-40 had a larger AUC than troponin-I, suggesting it might be a more valuable biomarker for the differentiation of high-risk PE patients.
In this study, we excluded patients with comorbidities that may affect YKL-40 level as identified in previous studies. However, the fact that ejection fraction values were not homogeneous between the groups is an important limitation. Increased smooth muscle hypertrophy as a result of low ejection fraction may have caused an increase in YKL-40 level. Therefore, studies comparing patient groups with comparable ejection fraction may validate our findings.
In conclusion, PE is an important disease associated with considerable morbidity and mortality, especially in high-risk patients, and this risk increases with delayed thrombolytic treatment. The decision for early thrombolytic therapy is made based on follow-up for patients at high-intermediate risk. YKL-40 may be a valuable biomarker that can guide thrombolytic therapy decisions in the early period for this patient group in particular. In addition, evaluated in light of previous reports, our results suggest that medical treatment targeting YKL-40 may also prevent thrombotic tendency in at-risk patient groups.