The NOTCH3 extracellular domain is a serum biomarker for pulmonary arterial hypertension

New biomarkers are needed to detect and follow individuals with World Health Organization group 1.1 pulmonary hypertension (idiopathic pulmonary arterial hypertension (IPAH)). As NOTCH3 cleavage occurs constitutively in the lungs of individuals with IPAH, we investigated whether the NOTCH3 extracellular domain (NOTCH3-ECD) shed into serum could be used as a robust biomarker for IPAH. In three geographically distinct cohorts comprising 341 individuals with IPAH (267 women, 74 men) and 376 healthy individuals (278 women, 98 men), serum NOTCH3-ECD levels were significantly higher in individuals with IPAH (mean ± s.d.: 19.9 ± 5.5 ng ml^-1) compared to controls (10.5 ± 1.9 ng ml^-1; P < 0.001), with consistent results among the three cohorts. NOTCH3-ECD levels correlated with mean right atrial pressure, pulmonary vascular resistance, mean pulmonary artery pressure, tricuspid regurgitant velocity, 6-min walk distance and the New York Heart Association class. The area under the receiver operating curve for diagnosis of IPAH, based on serum NOTCH3-ECD, was 0.96 (95% confidence interval, 0.95-0.98) with a 90% sensitivity and 93% specificity at a cutoff of 13.0 ng ml^-1. The 3-year mortality risk for individuals with IPAH increased by 18% for each increase in 3 ng ml^-1 of NOTCH3-ECD above the diagnostic cutoff. The addition of serum NOTCH3-ECD levels improved the performance of prognostic calculators for PAH, including REVEAL 2.0, REVEAL 2.0 Lite and COMPERA 2.0. Moreover, serum NOTCH3-ECD levels predicted the presence of IPAH in treatment-naive individuals and correlated with disease progression over a follow-up of 6 years. Measurement of serum NOTCH3-ECD can therefore provide a highly sensitive, specific and noninvasive test for predicting the presence, disease severity, progression and survival of individuals with IPAH.