Transpulmonary Proteome Gradients Identify Pathways Involved in Pulmonary Vascular Disease Due To Heart Failure.

Area of Science:

• Cardiology
• Pulmonology
• Proteomics

Background:

• Pulmonary vascular disease (PVD) complicates heart failure (HF), worsening prognosis.
• Mechanisms underlying PVD in HF remain poorly understood.
• Identifying PVD mediators is crucial for therapeutic development.

Purpose of the Study:

• To identify mediators of PVD in HF by analyzing transpulmonary protein gradients.
• To utilize unbiased proteomics for unbiased discovery of implicated proteins.
• To differentiate protein dynamics in HF patients with varying pulmonary vascular resistance (PVR).

Main Methods:

• Pulmonary artery catheterization in 160 HF patients and 21 controls.
• Blood sampling from post- and precapillary positions to determine transpulmonary gradients.
• Proteomic analysis (Olink assay) of 275 proteins in highest (Q4) and lowest (Q1) PVR quartiles.

Main Results:

• Pulmonary surfactant-associated protein D (PSP-D) identified as a PVD marker.
• High PVR HF lungs showed increased uptake of inflammatory proteins (chemokines, oncostatin-M, MMP9) and TGF/activin pathway proteins (GDF2/BMP9).
• Significant release of IL6 and IL33 observed in high PVR HF, with IL6 elevation correlating with right ventricular function.

Conclusions:

• HF lungs with high PVR exhibit abnormal inflammatory cytokine (IL6, IL33, oncostatin-M) exchange.
• Increased pulmonary uptake of GDF2/BMP9 suggests a role in vascular remodeling.
• Proteins involved in inflammation and vascular remodeling in pulmonary hypertension are also active in HF-associated PVD.