Endothelial Function in Patients With Pulmonary Arterial Hypertension

Serological and Non-invasive Evaluation of Endothelial Function in Patients With Pulmonary Arterial Hypertension

The objectives of the current study are to identify and evaluate new prognostic non-invasive and serological markers in patients with pulmonary hypertension. The focus will be on L-arginine metabolism and to clarify its influence on endothelial function.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Genetics; Pathophysiology
• Intervention / Treatment: Device: EndoPAT measurement; Biological: Blood Test

Detailed Description

The objectives of the current study are to identify and evaluate new prognostic non-invasive and serological markers in patients with pulmonary hypertension. The focus will be on L-arginine metabolism and to clarify its influence on endothelial function. The investigators also want to evaluate differences in plasma concentrations of L-arginine/NO metabolites and non-invasively assessed endothelial function based on specific PH-therapy.

Furthermore, the investigators aim to transfer the results gained from the investigators study population to in-vitro systems in order to carefully characterize the involved signal transduction pathways. Thereby the investigators hope to identify potentially new therapeutic targets in PH or patient subgroups preferably benefitting from established therapeutic options.

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Hamburg, Germany, 20246
    • Department of Respiratory Medicine, University Medical Center Hamburg-Eppendorf

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• proven PH (by right heart catheterization, PAP >25 mmHg, within last 12 months)
• age >18 years
• Dana Point classification I or IV (all subgroups)
• declaration of consent

Exclusion Criteria:

• Pulmonary Hypertension not proven by right heart catheterization
• Eisenmenger's syndrome/reaction
• PH other than Dana Point I and IV
• alcohol or drug abuse
• non-compliance due to any cause (e.g. severe psychiatric disorder)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Therapy-naive; This group consists of patients with a newly diagnosed PH (Class I or IV). First blood sampling takes place before initiation of PH therapy (0 months), the following measurements will be performed after 3, 6, 9 and 12 months under specific therapy. Initiation of standard therapy is performed directly after baseline visit / study inclusion. No special study medication will be used. Intervention: a) Device: EndoPAT measurement and b) Biological/Vaccine: Blood Test	Device: EndoPAT measurement; EndoPAT (Itamar Medical Ltd, Ceasarea, Isreal) quantifies the endothelium-mediated changes in vascular tone, elicited by a 5-minute occlusion of the brachial artery (using a standard blood pressure cuff). When the cuff is released, the surge of blood flow causes an endothelium-dependent Flow Mediated Dilatation (FMD). The dilatation, manifested as Reactive Hyperemia, is captured by EndoPAT as an increase in the PAT Signal amplitude. A post-occlusion to pre-occlusion ratio is calculated by the EndoPAT software, providing the EndoPAT index. EndoPAT is FDA-cleared and CE-marked.; Biological: Blood Test; It is hypothesized that L-arginine/NO-metabolites are altered in pulmonary hypertension depending on disease severity. Moreover, polymorphisms in L-arginine/NO-metabolism modifying factors may influence disease severity. Analysis will be performed following established/published protocols after isolation from whole blood.
ACTIVE_COMPARATOR: Under therapy; This group consists of patients under ERA monotherapy at timepoint of inclusion. Observation period is one year to detect intraindividual changes in endothelial dysfunction measured by L-arginine/NO-metabolites after 0, 3, 6, 9 and 12 months under investigation. Specific PAH therapy has been started prior to the study for medical reasons and will be continued throughout. Intervention: a) Device: EndoPAT measurement and b) Biological/Vaccine: Blood	Device: EndoPAT measurement; EndoPAT (Itamar Medical Ltd, Ceasarea, Isreal) quantifies the endothelium-mediated changes in vascular tone, elicited by a 5-minute occlusion of the brachial artery (using a standard blood pressure cuff). When the cuff is released, the surge of blood flow causes an endothelium-dependent Flow Mediated Dilatation (FMD). The dilatation, manifested as Reactive Hyperemia, is captured by EndoPAT as an increase in the PAT Signal amplitude. A post-occlusion to pre-occlusion ratio is calculated by the EndoPAT software, providing the EndoPAT index. EndoPAT is FDA-cleared and CE-marked.; Biological: Blood Test; It is hypothesized that L-arginine/NO-metabolites are altered in pulmonary hypertension depending on disease severity. Moreover, polymorphisms in L-arginine/NO-metabolism modifying factors may influence disease severity. Analysis will be performed following established/published protocols after isolation from whole blood.
ACTIVE_COMPARATOR: Healthy controls; This group consists of healthy individuals. Sex and age matching is intended. Intervention: a) Device: EndoPAT measurement and b) Biological/Vaccine: Blood	Device: EndoPAT measurement; EndoPAT (Itamar Medical Ltd, Ceasarea, Isreal) quantifies the endothelium-mediated changes in vascular tone, elicited by a 5-minute occlusion of the brachial artery (using a standard blood pressure cuff). When the cuff is released, the surge of blood flow causes an endothelium-dependent Flow Mediated Dilatation (FMD). The dilatation, manifested as Reactive Hyperemia, is captured by EndoPAT as an increase in the PAT Signal amplitude. A post-occlusion to pre-occlusion ratio is calculated by the EndoPAT software, providing the EndoPAT index. EndoPAT is FDA-cleared and CE-marked.; Biological: Blood Test; It is hypothesized that L-arginine/NO-metabolites are altered in pulmonary hypertension depending on disease severity. Moreover, polymorphisms in L-arginine/NO-metabolism modifying factors may influence disease severity. Analysis will be performed following established/published protocols after isolation from whole blood.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences of endothelial function regarding disease class and severity	Quantification of L-arginine metabolites in whole blood; PAT-Ratio as non-invasively assessed endothelial function by EndoPAT2000-Device (Itamar Medical Ltd., Caesarea, Israel) 0 months = Time of Inclusion	0, 3, 6, 9 and 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of endothelial function with changes in pulmonary hemodynamics	L-arginine metabolite concentrations and PAT-Ratio correlated with PAPm, RAP, PVR (assessed by right heart catheterization within 12 months prior to inclusion) and echocardiographical parameters RVSP, TAPSE and TEI.	0,3,6,9 and 12 months
Correlation of endothelial function with established prognostic factors	L-arginine metabolite concentrations and PAT-Ratio correlated with plasma concentration of proBNP as well as capillary pCO2, 6-minute walk distance and NYHA/WHO functional class.	0,3,6,9 and 12 months
Correlation of endothelial function with possible prognostic factors	L-arginine metabolite concentrations and PAT-Ratio correlated with plasma concentration of various enzymes as well as lung function.	0,3,6,9 and 12 months
Correlation of L-arginine metabolites with pulmonary vascular signaling	In vitro evaluation of human pulmonary vasculature cells signaling and proliferation by altered L-arginine metabolite levels.	0 months
Correlation of polymorphisms in L-arginine metabolism genes with disease severity		0 months
Correlation of endothelial function with possible novel diagnostic or prognostic factors (e.g., inflammatory markers, intermediary metabolites)		0 months

Collaborators and Investigators

• Sponsor: Universitätsklinikum Hamburg-Eppendorf
• Collaborators: Pfizer; Actelion
• Investigators: Study Director: Hans FE Klose, MD, Department of Respiratory Medicine, University Medical Center Hamburg-Eppendorf; Principal Investigator: Jan K Hennigs, MD, Department of Respiratory Medicine, University Medical Center Hamburg - Eppendorf

Publications and helpful links

Helpful Links

• Link to Publication of Study Results

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 1, 2010
• Primary Completion (ACTUAL): December 1, 2014
• Study Completion (ACTUAL): July 1, 2016

Study Registration Dates

• First Submitted: March 15, 2011
• First Submitted That Met QC Criteria: March 15, 2011
• First Posted (ESTIMATE): March 17, 2011

Study Record Updates

• Last Update Posted (ACTUAL): August 11, 2022
• Last Update Submitted That Met QC Criteria: August 8, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Genetics; Pulmonary Arterial Hypertension; Prognostic factors; Signal transduction
• 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: PNEU-PV3334/2009/UKE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO