Plasma TRAIL and ANXA1 in diagnosis and prognostication of pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a rare vasculopathy, with high morbidity and mortality. The sensitivity of the current european society of cardiology/european respiratory society (ESC/ERS) risk assessment strategy may be improved by the addition of biomarkers related to PAH pathophysiology. Such plasma-borne biomarkers may also reduce time to diagnosis, if used as diagnostic tools in patients with unclear dyspnea, and in guiding treatment decisions. Plasma levels of proteins related to tumor necrosis factor (TNF), inflammation, and immunomodulation were analyzed with proximity extension assays in patients with PAH (n = 48), chronic thromboembolic pulmonary hypertension (PH; CTEPH, n = 20), PH due to left heart failure (HF) with preserved (HFpEF-PH, n = 33), or reduced (HFrEF-PH, n = 36) ejection fraction, HF without PH (n = 15), and healthy controls (n = 20). TNF-related apoptosis-inducing ligand (TRAIL) were lower in PAH versus the other disease groups and controls (p < 0.0082). In receiver operating characteristics analysis, TRAIL levels identified PAH from the other disease groups with a sensitivity of 0.81 and a specificity of 0.53 [area under the curve: 0.70; (95% confidence interval, CI: 0.61-0.79; p < 0.0001)]. In both single (p < 0.05) and multivariable Cox regression models Annexin A1 (ANXA1) [hazard ratio, HR: 1.0367; (95% CI: 1.0059-1.0684; p = 0.044)] and carcinoembryonic antigen-related cell adhesion molecule 8 [HR: 1.0603; (95% CI: 1.0004-1.1237; p = 0.0483)] were significant predictors of survival, adjusted for age, female sex and ESC/ERS-initial risk score. Low plasma TRAIL predicted PAH among patients with dyspnea and differentiated PAH from those with CTEPH, HF with and without PH; and healthy controls. Higher plasma ANXA1 was associated with worse survival in PAH. Larger multicenter studies are encouraged to validate our findings.

Keywords: TNF‐signaling; biomarkers; immunomodulation; inflammation; pulmonary hypertension.

Figure 1

Study setup. A diagnostic (1) arm was followed by a prognostic (2) arm. ANXA1, Annexin A1; C, control; CTEPH, chronic thromboembolic pulmonary hypertension; HFpEF‐PH, pulmonary hypertension due to heart failure with preserved ejection fraction; HFrEF‐PH, pulmonary hypertension due to heart failure with reduced ejection fraction; HF‐non‐PH, heart failure without pulmonary hypertension; PAH, pulmonary arterial hypertension; ROC, receiver operating characteristics; TNF, tumor necrosis factor; TRAIL, TNF‐related apoptosis‐inducing ligand; 3‐year‐survivors: patients surviving 3 years from diagnosis.

Figure 2

TRAIL is lower compared to all other groups. p values are shown for each comparison. AU, arbitrary units; CTEPH, chronic thromboembolic pulmonary hypertension; HFpEF‐PH, pulmonary hypertension due to heart failure with preserved ejection fraction; HFrEF‐PH, pulmonary hypertension due to heart‐failure with reduced ejection fraction; HF‐no‐PH, heart failure without pulmonary hypertension; TRAIL, TNF‐related apoptosis‐inducing ligand.

Figure 3

ROC curve of TRAIL as a discriminator of PAH in a dyspnea population. ROC, receiver operating characteristic; TRAIL, TNF‐related apoptosis‐inducing ligand.

Figure 4

Kaplan–Meier curves. Kaplan–Meier curves of survival with protein's level's below or equal respective above threshold for survival in a ROC analysis. (a) ANXA1, (b) CEACAM8, (c) CXCL17, (d) GDF‐15, (e) IL‐6, (f) PSP‐D, (g) TRAIL‐R2. Abbreviations as in Table 3.