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.

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.

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

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

This group consists of healthy individuals. Sex and age matching is intended. Intervention: a) Device: EndoPAT measurement and b) Biological/Vaccine: Blood

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.

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.

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

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.

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.

L-arginine metabolite concentrations and PAT-Ratio correlated with plasma concentration of various enzymes as well as lung function.

In vitro evaluation of human pulmonary vasculature cells signaling and proliferation by altered L-arginine metabolite levels.

Correlation of endothelial function with possible novel diagnostic or prognostic factors (e.g., inflammatory markers, intermediary metabolites)

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)