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

Summary

Across three independent cohorts, serum NOTCH3-ECD concentrations were significantly elevated in patients with idiopathic pulmonary arterial hypertension compared with healthy individuals, supporting its role as a circulating biomarker. The findings align mechanistically with constitutive NOTCH3 cleavage in IPAH lungs and suggest utility for diagnosis and potentially for disease monitoring.

Key Findings

• Serum NOTCH3-ECD levels were significantly higher in IPAH versus healthy controls across three geographically distinct cohorts.
• The biomarker is mechanistically linked to constitutive NOTCH3 cleavage in IPAH lungs, supporting biological plausibility.
• Results suggest potential roles in diagnosis and disease monitoring of pulmonary arterial hypertension.

Clinical Implications

NOTCH3-ECD could complement current diagnostic pathways for pulmonary arterial hypertension, enabling noninvasive screening and longitudinal monitoring. Thresholds, assay standardization, and prospective evaluation in at-risk populations will be key for clinical adoption.

Limitations

• Observational design precludes causal inference
• Assay thresholds and external clinical validation for monitoring remain to be established

Future Directions

Prospective studies defining diagnostic thresholds, test performance against contemporary standards (e.g., right heart catheterization), and responsiveness to therapy will clarify clinical utility. Evaluation in related PH subtypes is warranted.