Angiopoietin-2 - a novel biomarker for risk stratification of acute pulmonary embolism

Abstract

Background and aim: Elevated levels of Angiopoietin-2 (Ang-2) are associated with impaired hemodynamic parameters and poor prognosis in patients with idiopathic pulmonary hypertension. We aimed to investigate the prognostic value of Ang-2 in patients with acute pulmonary embolism (PE). Methods: We studied 187 patients (54.0% women; median age, 69 [IQR, 52-78] years) with acute PE in a prospective single-centre cohort study. Ang-2 plasma concentrations were measured with an immunoluminometric assay (ILMA) at the time of admission (t0h) and after 24 hours (t24h). Results: Ang-2 t0h levels range from 0.1 to 25.9 (median, 2.5 [IQR, 1.6-4.4]) ng/ml and Ang-2 t24h levels from 0.01 to 54.2 (2.1 [1.2-3.7]) ng/ml. Ang-2 t0h concentrations correlated with GFR and NT-proBNP (r=0.463 and 0.522, respectively) and were higher in patients with chronic heart failure, renal insufficiency, and immobilization. Overall, 24 patients (12.8%) were classified as high-risk according to the ESC definition, 114 patients (61.0%) as intermediate-, and 49 patients (26.2%) as low-risk. High-risk patients had higher levels of Ang-2 compared to non-high-risk patients (t0h: 5.1 [3.7-7.0] vs. 2.3 [1.5-3.6] ng/ml, p<0.001; t24h: 7.5 [6.4-11.9] vs. 1.9 [1.2-3.1] ng/ml, p<0.001). For investigation of the prognostic value of Ang-2, further analyses were based on 163 non-high-risk patients; of those, 14 patients (8.6%) had an adverse 30-day outcome. Interestingly, neither Ang-2 t0h levels nor the increase of Ang-2 levels were associated with an adverse outcome, while Ang-2 t24h was, besides chronic heart failure, renal insufficiency, tachycardia, and troponin T elevation, identified as predictor of an adverse outcome (OR, 1.3 [95 CI, 1.1-1.5]; p=0.005). ROC analysis illustrated an area under the curve (AUC) of 0.72 [0.56-0,87] for Ang-2 t24h and a concentration of 2.55 ng/ml was identified as optimal cut-off value (OR, 5.3 [1.6-17.6]; p=0.007). Of 171 patients who survived the acute phase, 29 (17.0%) died and 5 (6.1%; n=82) developed a chronic thromboembolic pulmonary hypertension (CTEPH) during the follow-up period (442 [203-1090] days). Interestingly, Ang-2 t0h, but not Ang-2 t24h, was identified to predict development of CTEPH (OR, 1.4 [1.1-1.8]; p=0.017; AUC, 0.90 [0.73-1.00]). Moreover, Ang-2 t24h, but not Ang-2 t0h, emerged as predictor of all-cause mortality in long-term follow-up (HR, 1.1 [1.0-1.2]; p=0.019). Conclusion: Ang-2 might serve as a novel biomarker for risk stratification of patients with acute PE and furthermore, might be helpful for identification of patients who will develop CTEPH.