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

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. We aimed to analyze transpulmonary gradients of proteins consumed or elaborated across the lungs to identify mediators of PVD by unbiased proteomics. METHODS: Overall, 21 controls and 160 patients with HF with reduced ejection fraction underwent pulmonary artery catheterization with blood sampling from postcapillary (wedged balloon) and precapillary (unwedged) position to obtain transpulmonary gradients. The samples from controls and HF from the highest (Q4, n=40) and lowest quartile (Q1, n=40) of pulmonary vascular resistance (PVR) were analyzed using the proteomic proximity extension assay (Olink) of 275 proteins. Venous blood concentrations or transpulmonary gradients were analyzed to identify biomarkers or potential mediators of PVD. RESULTS: Comparison of Q1 and Q4 of PVR identified PSP-D (pulmonary surfactant-associated protein D) as a marker of PVD. Examination of gradients across the lungs in high PVR HF revealed significant uptake of 18 proteins, mostly associated with inflammation (chemokines, oncostatin-M, MMP9 matrix metalloproteinase 9) or with TGF (transforming growth factor)/activin pathway (GDF2 growth differentiation factor 2/BMP9 bone morphogenic protein 9), and release of 5 proteins, notably IL (interleukin) 6 and IL33. In contrast, these protein gradients were negligible in controls and low PVR patients with HF. Active pulmonary release of IL6 contributed to systemic elevation of IL6 and correlated with right ventricular function. CONCLUSIONS: The lungs of patients with HF with high PVR display abnormal uptake and release of proinflammatory cytokines from IL6/gp130 family (IL6, IL33, oncostatin-M), along with increased transpulmonary uptake of GDF2/BMP9. The study shows that proteins orchestrating inflammation or pulmonary vessel remodeling in group 1 pulmonary hypertension, are also operating in patients with PVD due to HF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06331208.