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We demonstrated that growth differentiation factor 15 (GDF‑15) levels may be accurately employed in predicting serious adverse outcomes and bleeding events in acute pulmonary embolism. We propose a threshold of GDF‑15 concentration above 1680 ng/l for that purpose. This is the first report focusing on the feasibility of measuring GDF‑15 concentrations in bleeding risk prediction.

Introduction

Growth differentiation factor 15 (GDF‑15) is a distant member of the transforming growth factor superfamily (TGF-β), first identified as a chemokine secreted by activated macrophages in response to oxidative stress.¹ A growing body of evidence confirms its diagnostic and prognostic value in patients with acute myocardial infarction, chronic coronary syndromes, chronic heart failure, and in relation to bleeding complications in patients with atrial fibrillation on anticoagulation.^2-9 Moreover, its role in risk stratification for fetal ventricular arrhythmias in patients with non‑ischemic dilated cardiomyopathy was also recently reported.¹⁰ Little is known about its feasibility in predicting adverse events in acute pulmonary embolism (PE). In terms of pathophysiology, it is generally accepted that both functional ischemia and myocarditis (inflammation) contribute to failure of the right ventricle (RV) in acute PE potentially leading to life‑threatening hemodynamic destabilization.^11-14 Therefore, it seems plausible to measure plasma GDF‑15 concentrations in patients with acute PE. There are few reports on the potential value of GDF‑15 measurements in venous thromboembolism^15-18 which point to the predictive value of plasma GDF‑15 concentrations in acute RV failure and high thrombotic burden in deep vein thrombosis, evaluating the potential relationship between GDF‑15 levels and the severity of RV dysfunction assessed with biomarkers and imaging modalities, and as such serve as a gateway for further elucidation of the role of GDF‑15 in right heart dysfunction and failure in acute PE. Moreover, they shed light on the potential role of serum GDF‑15 concentrations as a parameter in mortality prediction algorithms. The importance of refining these algorithms stems from the wide‑spread use of a risk‑adapted management strategy in PE, which ranges from home treatment to urgent primary reperfusion depending on current and anticipated PE severity.^19-23

Furthermore, elevated GDF‑15 levels have been repeatedly linked to bleeding events in a wide spectrum of patients with atrial fibrillation on anticoagulative treatment and in patients with acute coronary syndromes, as reported in the ARISTOTLE (Apixaban versus Warfarin in Patients with Atrial Fibrillation) and PLATO (Platelet Inhibition and Patient Outcomes) trials, respectively.^24,25 Recently, it was suggested that a predictive value of GDF‑15 in atrial fibrillation could be in part attributed to its association with prothrombotic blood alterations.²⁶ The clinical benefit of those findings is the development of the ABC bleeding score (age, biomarkers, clinical history) which incorporates GDF‑15 levels for predicting bleeding events in the atrial fibrillation population.²⁷ Hemorrhagic complications are also a burden of anticoagulative treatment in PE. Therefore, the aims of this study were as follows: 1) evaluation of plasma GDF‑15 levels in acute RV failure in a wide spectrum of clinical, hemodynamic, and biochemical scenarios; 2) association of plasma GDF‑15 levels with established biomarkers of RV overload and dysfunction (both laboratory as well as quantitative parameters of RV dysfunction in imaging studies); 3) association of plasma GDF‑15 levels with bleeding events in patients with PE on anticoagulation.

Patients and methods

Results

The final study group included 77 patients: 18 low‑risk patients classified according to the ESC algorithm, 27 intermediate‑low–risk patients, 24 intermediate‑high–risk patients, and 8 high‑risk patients were included. The median (IQR) length of hospital stay was 9 (6–15) days. The flow of patients is presented in Figure 1. Baseline characteristics are presented in Table 1. Bleeding risk factors are presented in Table 2.

There were 12 SAE (including 2 cardiopulmonary resuscitations, 2 deaths, 7 percutaneous embolectomies, 1 surgical pulmonary embolectomy) and 5 bleeding events (2 MB and 3 CRNMB). The median (IQR) GDF‑15 concentration at admission was 2354 (1151–4750) ng/l. Concentrations of GDF‑15 increased according to risk subgroup assessed using the ESC algorithm: for low‑risk patients, the median (IQR) GDF‑15 concentration was 1281 ng/l (998–1999 ng/l), for intermediate‑low–risk, 2354 ng/l (1115–4824 ng/l), for intermediate‑high–risk, 2926 ng/l (1395–4692 ng/l), for high‑risk patients, 8998 ng/l (5007–16 039 ng/l). Differences in concentrations between the 4 subgroups were significant (P = 0.009).

Patients who experienced serious adverse events or bleeding events, as well as patients with higher concentrations of established biomarkers of myocardial overload and injury and hypotensive patients had higher baseline concentrations of GDF‑15. Additionally, the same observation was made in patients with diagnosed AF, impaired kidney function, anemia, or elevated D‑dimer levels (Table 3). The analyzed echocardiographic signs of RV overload or dysfunction alone, or DVT did not significantly influence plasma GDF‑15 levels.

The AUC for GDF‑15, cTnT‑hs, and NT‑proBNP concentrations for predicting SAE was similar: for GDF‑15, AUC was 0.679 (95% CI, 0.505–0.854; P = 0.04). For cTnT‑hs, AUC was 0.762 (95% CI, 0.596–0.928; P = 0.002). For NT‑proBNP, AUC was 0.706 (95% CI, 0.567–0.844; P = 0.004). Pairwise comparisons revealed no significant differences in AUC for ROC curves for the biomarkers (GDF‑15 vs cTnT‑hs, P = 0.53; GDF‑15 vs NT‑proBNP, P = 0.84) (Figure 2). The AUC for GDF‑15 levels for predicting bleeding was 0.783 (95% CI, 0.62–0.946; P = 0.001) (Figure 3), and 0.71 (95% CI, 0.567–0.853; P = 0.004) for predicting any adverse event (Figure 4). The optimal threshold for GDF‑15 in predicting any adverse event (SAE or bleeding) was chosen based on the ROC curve analysis. The value of 1680 ng/l had 94% sensitivity, 41% specificity, negative predictive value of 96%, and positive predictive value of 29%. In the multivariable analysis, GDF‑15 levels higher than 1680 ng/l emerged as an independent predictor of a complicated clinical outcome (Table 4).

Discussion

The key finding of this study is that plasma GDF‑15 levels are useful in identifying patients at risk of serious adverse and hemorrhagic events in the course of acute PE. In terms of predicting bleeding risk in patients with acute PE, to the best of our knowledge, this is the first report focusing on the role of measuring GDF‑15 concentrations in this setting.

It has been shown that ischemic injury, mechanical stretch, neurohormones, and proinflammatory cytokines stimulate the expression of GDF‑15 in cardiac myocytes.^31,32 The proposed biological activities of GDF‑15 are as follows: 1) the role of GDF‑15 in vivo was first described in 2006 using a murine model, in which it was demonstrated that GDF‑15 is induced in cardiomyocytes in response to cardiac ischemia, serving a protective function by inhibiting PI3K/Akt kinase‑dependent apoptosis³¹; 2) the cardioprotective effect of GDF‑15 may be attributed to its capacity to inhibit apoptosis and cardiac hypertrophy through the SMAD protein–related pathways, similar to other members of the TGF superfamily³³; 3) during cardiac ischemia, GDF‑15 is induced locally in the heart and exhibits anti‑inflammatory properties by inhibiting leukocyte β₂ integrin activation required for leukocyte recruitment.³⁴ Inflammation and ischemia are the cornerstones of RV dysfunction leading to failure in acute PE.³⁵

Our conclusions are in line with others, who have reported the feasibility of employing GDF‑15 levels in predicting adverse events in other cardiovascular diseases, such as myocardial infarction, chronic coronary syndromes, chronic heart failure, acute PE, and atrial fibrillation.^{2-9,15-18,24,25}

In our study, GDF‑15 showed a satisfactory discriminatory capacity in predicting SAE and any hemorrhagic event (MB and CRNMB) in acute PE, as demonstrated by the AUC of 0.783 (95% CI, 0.62–0.946; P = 0.001) for bleeding complications and of 0.710 (95% CI, 0.567–0.853; P = 0.004) for predicting any adverse event. Its diagnostic performance in predicting SAE was similar to cTnT‑hs. Based on the ROC curve analysis, we propose a threshold of 1680 ng/l for predicting SAE or hemorrhagic complications. Using multivariable analysis, we demonstrated that a GDF‑15 level above 1680 ng/l is an independent predictor of a complicated outcome.

The proposed value of 1680 ng/l for acute PE is similar to that suggested by the results of landmark randomized clinical trials in AF. In the RE‑LY trial of 8474 patients, GDF‑15 concentrations above 1800 ng/l were associated with the highest risk of the occurrence of adverse events.³⁶ A similar observation in regard to the cutoff value was made in a subanalysis of the ENGAGE AF TIMI‑48 trial, which included 8705 patients and demonstrated that baseline GDF‑15 levels above 1800 ng/l predicted the 12‑month occurrence of bleeding events better than concentrations within the lower tercile of below 1200 ng/l.³⁷ Lastly, in the ARISTOTLE trial, out of the tested variables GDF‑15 was the most strongly associated with bleeding‑related death, with median baseline levels of 2215 ng/l in the described limited subgroup of 31 patients.³⁸

Several study limitations should be acknowledged. First, there was a limited number of enrolled patients making this a preliminary report. Second, GDF‑15 levels are influenced by circadian rhythm and fasting. Thus, all patients should be tested within the same time frame of several hours. In this study, all blood samples were collected between 7:30 am and 12:00 pm; however, this slight discrepancy could influence the observed GDF‑15 levels. Finally, this study also enrolled patients with AF, which may influence GDF‑15 levels. However, AF and PE frequently co‑exist and the inclusion of such patients reflect the real‑world nature of this study.³⁹