Circulating Angiopoietin-2 (Angpt2) levels predict diagnosis of Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Abstract Background Vascular remodeling following incomplete thrombus resolution is considered to be a key factor in the progression to chronic thromboembolic pulmonary hypertension (CTEPH) after acute pulmonary embolism (PE). Recent data demonstrated that Angpt2, which controls signaling via the Tie2 receptor, could interfere with the normal process of thrombus resolution. Our prior findings have shown that patients presenting with acute PE and having plasma levels of Angt-2 ≥5.5 ng/ml at admission are at a significantly increased risk (93 times higher) of being diagnosed with CTEPH in subsequent assessments. Purpose To externally validate the prognostic performance of Angpt2 for the development of CTEPH. Methods In a prospective cohort study of unselected consecutive all-comers with PE, survivors of the index acute event underwent 3-, 12- and 24-month follow-up with venous blood sampling for subsequent biomarker measurements. Angpt2 was measured on admission using specific enzyme linked immunosorbent assays (ELISA) detecting both the endogenous and the recombinant protein, according to the manufacturer (R&D Systems). Results Overall, 319 patients with acute PE (median age: 62 [IQR, 50-73]; females: 55.2%) were included in the analysis with a median Angpt2 plasma level of 2.6 ng/ml (IQR, 1.8-3.7) (Figure 1). Patients with PE and Angpt-2 plasma levels above the median had more often comorbidities, such as chronic heart failure (24.2% and 11.0.%; p=0.045), chronic kidney disease (33.3% vs 14.0%; p=0.010), or diabetes (27.3% vs. 12.9%; p=0.032). Angpt2 plasma levels correlated with haemodynamic status and parameters indicating severe PE (right ventricle dysfunction, r=0.129 [p=0.021) and troponin, r=0.246 [p<0.001]). In total, post-PE impairment (PPEI) was diagnosed in 33 (10.3%) and CTEPH in four (1.3%) patients during follow-up. Angpt2 plasma levels were higher on admission in patients developing PPEI or CTEPH during follow-up compared to patients without PPEI or CTEPH (PPEI vs non-PPEI: median, 3.2 [2.3-4.1] ng/ml vs. 2.5 [1-3.4] ng/ml, p=0.035; CTEPH vs. non-CTEPH: median, 5.1 [2.9-10.5] ng/ml vs. 2.5 [1.7-3.6] ng/ml, p=0.055). Regarding the diagnosis of CTEPH during follow-up, ROC analysis illustrated an AUC for Angpt2 (0.779 [95% CI 0.56–0.99]; p=0.055]) (Figure 2). By using univariate logistic regression analysis, the calculated predefined Angpt2 cut-off value of ≥5.5 ng/ml was associated with a 9.2-fold increased risk (1.3–67.4, p=0.030) for a diagnosis of CTEPH during follow-up. Conclusion We were able to validate in a different patient cohort the usefulness of Angpt2 as a novel biomarker to identify patients at risk for CTEPH.