INFLAMMATORY PATHWAYS ARE INVOLVED IN THE DEVELOPMENT OF PULMONARY VASCULOPATHY IN HEART FAILURE: TRANSPULMONARY PROTEOMICS STUDY

Background: Some, but not all, patients with heart failure (HF) develop pulmonary vascular disease (PVD), which contributes to poor prognosis. Mechanisms leading to PVD in HF are poorly understood. Analysis of transpulmonary gradients may identify mediators of PVD  that are consumed or elaborated across the lung vascular bed.

Methods: 21 non-HF controls and 160 patients with advanced HFrEF underwent pulmonary artery (PA) catheterization with blood sampling from the PA catheter in the wedged (02sat > 90%) or un-wedged position to obtain transpulmonary gradients. Samples from controls and HF from the highest quartile (Q4, n=40) and lowest quartile (Q1, n=40) of pulmonary vascular resistance (PVR) were analyzed using PEA assay of 275 proteins (Olink Target 96, panels CVII, CVIII, Inflammation). PA transpulmonary fold-change gradients were plotted against significance (Vulcan plots). 

Results: Patients (age 56±8y, NYHA 3.0 ±0.6, 87% males, LVEF 24±9.6%) an controls had similar anthropometrics, gender and age. HF patients in Q1 had median PVR 1.5 (IQR: 0.3-1.7) WU and those in Q4 had PVR 5.4 (4.3-6.6) WU. Protein gradients from HF lungs showed significant uptake of 14 mediators, most of which were associated with inflammatory responses (top 5: OSM, MMP9, CCL19, BNP, TR), and release of 8 mediators (top 4: IL-6, IL33, CCL4, CXCL10). Protein gradients were negligible in controls. Patients in Q4 PVR group were characterized by the highest pulmonary uptake of OSM (Oncostatin-M), CCL19, BNP, MMP9, and significant transpulmonary release of IL6 and IL33.

Conclusions: Lungs of patients with HF, and particularly those with high PVR, display abnormal release of proinflammatory chemokines IL6 and IL33, along with increased pulmonary uptake of Oncostatin-M, known mediator of lung inflammation/fibrosis, suggesting a novel role in PVD due to HF.