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.

Circulating Biomarkers in Pulmonary Arterial Hypertension: An Update

“…The plasma levels of proteins related to tumor necrosis factor (TNF), inflammation, and immunomodulation were analyzed in patients with PAH, chronic thromboembolic pulmonary hypertension, PH due to left heart failure (HF) with preserved (HFpEF-PH) or reduced (HFrEF-PH) ejection fraction, HF without PH, and healthy controls. Specifically, the TRAIL levels were lower in PAH patients versus patients with other diseases and controls [96]. In receiver operating characteristics analysis, the TRAIL levels identified PAH patients from those in other disease groups.…”

“…TRAIL identified PAH patients among patients with dyspnea and differentiated them from those with CTEPH, HF with and without PH, and healthy controls. [96] TRAIL could be useful for the diagnosis of PAH, but it is not widespread and is usually not used in clinical practice. Also, in the prognostic stratification of PAH patients, we support the idea that an integrated approach of imaging and biomarkers would be the best and safest approach.…”