Transpulmonary generation of cell‐free hemoglobin contributes to vascular dysfunction in pulmonary arterial hypertension via dysregulated clearance mechanisms

Abstract

Circulating cell‐free hemoglobin (CFH) is elevated in pulmonary arterial hypertension (PAH) and associated with poor outcomes but the mechanisms are unknown. We hypothesized that CFH is generated from the pulmonary circulation and inadequately cleared in PAH. Transpulmonary CFH (difference between wedge and pulmonary artery positions) and lung hemoglobin α were analyzed in patients with PAH and healthy controls. Haptoglobin genotype and plasma hemoglobin processing proteins were analyzed in patients with PAH, unaffected bone morphogenetic protein receptor type II mutation carriers (UMCs), and control subjects. Transpulmonary CFH was increased in patients with PAH ( p = 0.04) and correlated with pulmonary vascular resistanc (PVR) ( r s = 0.75, p = 0.02) and mean pulmonary arterial pressure (mPAP) ( r s = 0.78, p = 0.02). Pulmonary vascular hemoglobin α protein was increased in patients with PAH ( p = 0.006), especially in occluded vessels ( p = 0.04). Haptoglobin genotype did not differ between groups. Plasma haptoglobin was higher in UMCs compared with both control subjects ( p = 0.03) and patients with HPAH ( p < 0.0001); patients with IPAH had higher circulating haptoglobin levels than patients with HPAH ( p = 0.006). Notably, circulating CFH to haptoglobin ratio was elevated in patients with HPAH compared to control subjects ( p = 0.02) and UMCs ( p = 0.006). Moreover, in patients with PAH, CFH: haptoglobin correlated with PVR ( r s = 0.37, p = 0.0004) and mPAP ( r s = 0.25, p = 0.02). Broad alterations in other plasma hemoglobin processing proteins (hemopexin, heme oxygenase‐1, and sCD163) were observed. In conclusion, pulmonary vascular CFH is associated with increased PVR and mPAP in PAH and dysregulated CFH clearance may contribute to PAH pathology. Further study is needed to determine whether targeting CFH is a viable therapeutic for pulmonary vascular dysfunction in PAH.

Caught in a vicious cycle: Cell‐free hemoglobin and the pathogenesis of pulmonary hypertension

“…In the past decade, investigators have uncovered a role for hemolysis in the pathophysiology of PAH in relation to the adverse effects of CFH, with exact mechanisms remaining incompletely understood. It is in this context that we read with great enthusiasm the article by Dr. Meegan and her colleagues on the role of transpulmonary generation of CFH as a novel mechanism for vascular dysfunction in PAH 2 …”

“…Meegan and her colleagues on the role of transpulmonary generation of CFH as a novel mechanism for vascular dysfunction in PAH. 2 In the current issue of Pulmonary Circulation, Meegan et al identify a novel mechanism whereby CFH contributes to PAH pathology. A prospective cohort of PAH patients underwent right heart catheterization and plasma CFH levels were measured at the pulmonary artery and wedge positions.…”