Serum Bio-markers in Pulmonary Hypertension

Role of Inflammation and Angiogenesis in Chronic Thromboembolic 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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Hypertension, Primary, 4

Detailed Description

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 (Actual): 377

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridge, United Kingdom, CB2 0AY
    • Royal Papworth Hospital NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients diagnosed with CTEPH, CTED and healthy control volunteers at the Royal Papworth Hospital.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
CTEPH; Patients diagnosed with chronic thromboembolic pulmonary hypertension
CTED; Patients diagnosed with chronic thromboembolic disease but no evidence of pulmonary hypertension
Control; Healthy control subjects

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	24 hours

Collaborators and Investigators

• Sponsor: Papworth Hospital NHS Foundation Trust
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Joanna Pepke-Zaba, PhD FRCP, Royal Papworth Hospital NHS Foundation Trust

Publications and helpful links

General Publications

• Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M; ESC Scientific Document Group. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016 Jan 1;37(1):67-119. doi: 10.1093/eurheartj/ehv317. Epub 2015 Aug 29. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): April 4, 2012
• Primary Completion (Actual): August 31, 2017
• Study Completion (Actual): October 26, 2017

Study Registration Dates

• First Submitted: July 6, 2020
• First Submitted That Met QC Criteria: July 10, 2020
• First Posted (Actual): July 15, 2020

Study Record Updates

• Last Update Posted (Actual): July 15, 2020
• Last Update Submitted That Met QC Criteria: July 10, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: inflammation; angiogenesis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary
• Other Study ID Numbers: T01502

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: No plan to share individual participant data

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No