The findings of this study revealed that higher levels of NT-proBNP and GDF-15 were significantly associated with high-risk APE. GDF-15 and NT-proPNP levels were found to have high predictive powers in predicting the development of adverse events and mortality, respectively, in patients with APE.
The serum levels of the natriuretic peptides indicate increased ventricular load in acute and chronic thromboembolic events [9, 11, 12]. In parallel, it was speculated that there is a possible association between the right ventricular dysfunction secondary to APE and the increased levels of the natriuretic peptides [4, 8]. Jenab et al.[8] and Vuilleumier et al.[13] found that the increased levels of NT-proBNP and APE-related short- and long-term adverse outcomes and mortality were significantly associated. Nevertheless, they did not find any significant relation between other cardiac markers, including GDF-15, H-FABP, tenascin-C, and D-dimer, and the prognosis of APE. Bi et al.[11] reported that higher BNP, TnI, and D-dimer levels were positively correlated with the severity of APE and APE-related mortality. Andresen et al.[4] found that NT-proBNP decreased significantly following the successful treatment of APE using an invasive treatment method. This finding may suggest a negative correlation between NT-proBNp levels and revascularization success. Vuilleumier et al.[5] showed the negative predictive power of NT-proBNPon identifying low-risk patients with non-massive APE. In comparison, in this study, NT-proBNP was found to be the most potent independent predictive factor for hospitalization during the three-month follow-up period compared to other biomarkers, including cardiac troponins, H-FABP, myoglobin, and D-dimer. Additionally, increased NT-proBNP levels were found to be associated with high-risk APE, predicting the mortality in APE patients. Although the exact pathophysiological mechanisms for the increase in the natriuretic peptide levels and the associations thereof with the ventricular dysfunction remain obscure, the findings of this study and the respective findings reported in the literature suggest that NT-proBNP can be used as a marker for the severity of APE [5, 11].
GDF-15 has been identified as a molecule that reflects pressure overload or myocardial ischemia [8, 14, 15]. Increased levels of GDF-15 in patients with APE might be related to underlying conditions like heart failure, renal insufficiency, or malignancy. In parallel, patients with such conditions were excluded from this study in order to assess the predicting power of GDF-15 [8]. A significant relation was found between higher GDF-15 levels and the development of adverse events in the positive direction, contrary to some of the findings reported in the literature [8]. Similarly, Lankeit et al.[14] reported that GDF-15 is a promising marker for the risk stratification of APE. GDF-15 was the only independent predictor for a complicated APE course compared with other cardiac biomarkers such as cardiac troponins and NT-proBNP. Duran et al.[15] demonstrated the superiority of GDF-15 than NT-proBNP in predicting early death in normotensive APE patients. Although the sensitivity rates of GDF15, cTnT, and NT-proBNP were found to be similar in predicting severe adverse events, GDF-15 may be a promising predictor for the early prediction of hemodynamic destabilization and bleeding complications in APE [15]. In summary, it would be better to interpret the GDF-15 levels together with NT-proPNP levels in the risk stratification of APE patients.
Cardiac troponins are well-known biomarkers for cardiac injury. Several authors demonstrated the relationship between higher levels of cTnT and the severity of APE [9, 11]. Bi et al.[11] suggested that higher troponin levels may be attributed to the impairment of the right ventricular myocardial injury in APE patients. The interval between the onset of the symptoms and the peak levels of cardiac troponins seems to be the key indicating the respective levels in these patients [14]. In parallel, several authors did not find the elevation of cardiac troponins as remarkable in APE patients, which is compatible with the findings of this study [3].
H-BABF is significantly associated with the severity of APE [3, 8–10]. In Liu's meta-analysis, higher H-FABP levels were reported to be associated with at least a 10-fold increased risk of adverse events in patients with APE [16]. Due to the close association between H-FABP and cardiac injury, higher levels of this biomarker are likely in APE patients with cardiac dysfunction. Qian et al.[3] demonstrated the superiority of H-FABP as a predictor over cardiac troponins in APE patients. Similar results have been reported by other researchers [10].
In comparison, no such relation was detected in this study, probably due to the severity of the right ventricular dysfunction. Similar findings have also been reported by several other authors [8]. These controversial results might be attributed to the low number of primary outcomes or different inclusion and exclusion criteria outlined in other studies.
It has been suggested that the elevated levels of biomarkers such as troponins, myoglobin, and H-FABP in association with cardiomyocytes damage could provide more significant prognostic information in patients with APE [3, 17, 18]. Nonetheless, it is evident that the impact of APE on the cardiac system should be given due consideration in this suggestion. In this study, NT-proBNP was found to be the most potent predictor of unfavorable outcomes in APE compared to troponins, myoglobin, and H-FABP, in line with the literature data [5, 17]. This finding may be regarded as evidence for the presence of right ventricular dysfunction in the study group.
Seropian et al.[7] studied the impact of high cardiac troponin levels together with low NT-proBNP levels (high troponin discordance) on the outcomes of APE patients. They reported that high troponin discordance was significantly associated with the worse outcomes in these patients. The use of different cut-off values for these biomarkers might be the reason for such contradictory results. Taking the different predictive powers of biomarkers into consideration, Liu et al.[6] recommended using a joint test, which included a number of abnormal biomarkers, for a better prediction of the long-term risk of APE recurrence and all-cause mortality. Rapid progression of the disease leading to variations in the levels of the biomarkers may also be the reason for such controversial outcomes.
The prospective design of this study was one of its major strengths. Nevertheless, there were also some limitations to this study. First, it was carried out as a single-center study with a relatively small sample. Secondly, the dynamic and quantitative tests of the biomarkers studied within the scope of this study to evaluate the time curve of the changes during an APE attack were not conducted. Due to these biomarkers' short half-lives and circadian rhythm, serial measurements might be more effective in monitoring such associations [15, 19].
In conclusion, the higher levels of NT-proBNP and GDF-15 were found to be associated with more severe APE, worse outcomes, and mortality. Thus, these biomarkers can be used as indicators for predicting morbidity and mortality in relation to. Further large-scale studies are needed to clarify the potential roles of these biomarkers before they are considered for use in the risk stratification system for APE.