The NOTCH3 extracellular domain is a significant biomarker for three-year mortality risk in individuals with idiopathic pulmonary arterial hypertension.
Cohort
Does serum NOTCH3-ECD level accurately diagnose and predict disease severity and survival in individuals with idiopathic pulmonary arterial hypertension?
Serum NOTCH3-ECD is a highly sensitive and specific noninvasive biomarker that accurately diagnoses idiopathic pulmonary arterial hypertension and strongly predicts disease progression and mortality.
Effect estimate: HR 0.76 (95% CI 0.68-0.85)
p-value: p=<0.001
Abstract 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.
Hernandez et al. (Fri,) conducted a cohort in Idiopathic pulmonary arterial hypertension. NOTCH3 extracellular domain was evaluated on Three-year mortality risk in IPAH individuals (HR 0.76, 95% CI 0.68-0.85, p=<0.001). The NOTCH3 extracellular domain is a significant biomarker for three-year mortality risk in individuals with idiopathic pulmonary arterial hypertension.