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.
Study Type
OBSERVATIONAL
Enrollment
377
Royal Papworth Hospital NHS Foundation Trust
Cambridge, United Kingdom
Assess the differences between circulating biomarkers between patients with CTEPH, CTED and controls
Assess differences in inflammatory cytokines (IL6, 8, 10, TNFa, hsCRP \[all measured in pg/ml\]) and markers of angiogenesis (Ang2, BMP9, Endoglin, VEGFa, VEGFc, VEGFd \[all measured in pg/ml\]) in patients with CTEPH compared to healthy controls
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between IL6 and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum IL6 and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between IL8 and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum IL8 and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between IL10 and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum IL10 and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between TNFa and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum TNFa and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between Ang2 and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum Ang2 and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between BMP9 and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum BMP9 and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between Endoglin and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum Endoglin and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between VEGFa and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum VEGFa and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between VEGFc and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum VEGFc and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between VEGFd and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum VEGFd and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between hsCRP and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum hsCRP and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Time frame: 24 hours
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