Serum Bio-markers in Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by scarred blood clots in the blood vessels supplying the lungs. This in turn leads to failure of the right side of the heart. The reason why these scarred clots form is unknown. An operation to remove the scarred clots, known as pulmonary endarterectomy, is a potential cure. However, some patients have persistent obstructions within the blood vessels and heart failure even after surgery.

It is thought that abnormal levels of proteins, found in the blood stream and responsible for inflammation and the development of new blood vessels may have role in causing the disease. In this study, these proteins were measured to assess whether they provide clues as to the cause of the disease and whether they could be used for the risk stratification of patients.

Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed form of pulmonary hypertension whose pathogenesis remains to be fully elucidated. Altered endothelial homeostasis, defective angiogenesis and inflammation have been implicated. The formation of the organised occlusions is considered to arise from a failure to resolve acute pulmonary emboli. There is emerging evidence supporting the role of mediators of angiogenesis, inflammation and the coagulation cascade (and their many interactions) in CTEPH. Pulmonary endarterectomy (PEA), to remove these occlusions, may be a cure in some patients. Assessing circulating proteins associated with these processes may be not only useful for understanding disease pathogenesis but may also lead to improvements in clinical assessment.

The study was approved by the Regional Ethics Committee (Papworth Hospital Research Tissue Bank; 08/H0304/56+5). Consecutive patients undergoing PEA surgery at Royal Papworth Hospital National Health Service Foundation Trust, United Kingdom, who consented for participation in the Research Tissue Bank between February 2012 and August 2014, were recruited. A validation data set included all consecutive samples collected from CTEPH patients prior to PEA between April 2010 and Aug 2017. Patients were diagnosed in accordance with international guidelines.

Patients had serum samples collected from a peripheral vein prior to PEA. In a subset of patients, further sampling was performed at the first follow up visit to Papworth Hospital 3-6 months post-PEA. Customized human cytokine/chemokine magnetic bead assays and customized human angiogenesis/growth factor assays were used to measure levels of circulating proteins in these serum samples (interleukin \[IL\] 6, IL8, IL10, tumour necrosis factor \[TNF\] α, angiopoietin 2 \[Ang2\], endoglin, vascular endothelial growth factor \[VEGF\] a, VEGFc, VEGFd and bone morphogenetic protein 9 \[BMP9\]).

Levels were compared to levels from patients with chronic thromboembolic disease but no pulmonary hypertension (CTED) and healthy age and sex matched controls. In addition multivariate rank regression models were used to assess associations between levels of circulating proteins and clinical assessments carried out as part of the patients routine clinical care.

Eligibility Criteria:
Inclusion Criteria:

* Patients able to give informed written consent
* Patients diagnosed with chronic thromboembolic pulmonary hypertension (CTEPH) according to international guidelines at an expert pulmonary hypertension centre
* Patients diagnosed with chronic thromboembolic disease (CTED) according to international guidelines at an expert pulmonary hypertension centre
* Age and sex matched healthy volunteers

Exclusion Criteria:

* Patients with inflammatory comorbidities
* Patients taking immunosuppressant medication