Large-scale proteomic profiling across several independent observational cohorts identified 22 proteins associated with echocardiography-derived pulmonary artery systolic pressure, several of which were linked to invasive pulmonary vascular disease measures, vascular remodeling, and subsequent pulmonary hypertension risk, with genetic support for a potential causal role of NOTCH3 and two protein-defined endotypes of PH risk.
Proteomic profiling across several independent observational cohorts identified 22 proteins associated with echocardiography-derived pulmonary artery systolic pressure (PASP).
Several of the PASP-associated proteins were independently associated with invasive measures of pulmonary vascular disease.
Several PASP-associated proteins were associated with structural remodeling of the pulmonary vasculature.
Several PASP-associated proteins were associated with subsequent risk of developing pulmonary hypertension.
Genetic analyses support a potential causal role for NOTCH3 in pulmonary pressure/pulmonary hypertension.
A common splice-regulating genetic variant was identified that may modify susceptibility to pulmonary vascular stressors.
Protein-based clustering revealed two distinct biological subtypes (endotypes) associated with increased risk of pulmonary hypertension.
Pulmonary hypertension is high blood pressure in the lungs' blood vessels. It is serious and hard to diagnose, partly because no blood tests exist to detect it early. This study measured thousands of proteins in blood samples from several large groups of people and looked for proteins linked to lung artery pressure estimated by heart ultrasound. The researchers found 22 proteins associated with this pressure. Several of them were also linked to direct measurements of lung blood vessel disease, to structural changes in the lung vessels, and to the chance of later developing pulmonary hypertension. Genetic analyses suggested that a protein pathway called NOTCH3 may play a causal role, and they identified a common genetic variant that might affect how susceptible the lungs are to stress. Grouping people by their protein patterns revealed two distinct biological subtypes, both linked to higher risk of pulmonary hypertension. This research suggests these proteins could become candidate blood markers for earlier detection of pulmonary hypertension, and that changes in the lung vessels may begin early in the disease. The findings come from observational studies, so they show associations, and the genetic evidence for NOTCH3 is described as a potential causal role. More work is needed before these markers could be used in clinical practice.
Giugni F, Santos M, Yang Y, Lamberson V, Claggett B, Hoogeveen R, et al.. (2026). Large-scale proteomics identifies circulating markers of pulmonary pressure and pulmonary hypertension risk.. Nature communications. https://doi.org/10.1038/s41467-026-78432-w