Background:
Cyclophilin A (CyPA, encoded by Ppia) is secreted from pulmonary vascular smooth muscle cells in response to several stimuli including mechanical stretch and hypoxia. Recently, we demonstrated that extracellular CyPA and vascular Basigin (Bsg, encoded by Bsg) are crucial for hypoxia-induced PH by inducing growth factor secretion, inflammatory cell recruitment and VSMC proliferation in mice. Moreover, we demonstrated that high plasma CyPA levels are significantly associated with poor outcome (death or lung transplantation) in patients with pulmonary arterial hypertension (PAH). In this study, we examined plasma levels of CyPA in patients with chronic thromboembolic pulmonary hypertension (CTEPH) before and after percutaneous transluminal pulmonary angioplasty (PTPA), which is recently developed as a catheter-based therapy.
Methods and Results:
In consecutive 86 PTPA sessions in 24 patients, we examined the relationship between plasma CyPA levels, the severity of CTEPH and hemodynamic improvements after PTPA. We measured plasma CyPA levels by an immunoassay based on the sandwich technique. Plasma CyPA levels (ng/mL) were significantly elevated in patients with CTEPH (13.8±6.0, n=24) compared with those without PH (4.9±4.0, n=7) or healthy controls (4.6±2.8, n=18) (both P<0.001). Moreover, the severity of CTEPH assessed by pulmonary vascular resistance (PVR) correlated with plasma levels of CyPA, IFN-α2, stem cell factor and adipsin (all P<0.05). PTPA significantly reduced mean pulmonary artery pressure (P<0.05), PVR (P<0.01) and improved long-term prognosis compared with historical controls. Importantly, PTPA significantly reduced plasma CyPA levels in patients with CTEPH (5.4±4.1, P<0.001), suggesting that plasma CyPA is useful for evaluation of therapeutic effects of PTPA. Finally, we observed significant increase in anti-inflammatory cytokines (interleukin-4, 7, 13) and reduction in stem cell growth factor-β and adipsin (all P<0.05) after PTPA, suggesting improved metabolic and inflammatory state in CTEPH patients.
Conclusions:
These results indicate that plasma levels of CyPA are significantly increased in CTEPH patients and could be considered as an effective biomarker for assessment of the effects of PTPA.
Plasma levels of high density lipoprotein cholesterol and outcomes in chronic thromboembolic pulmonary hypertension
