Biomarker activity in adult patients with pulmonary hypertension.

Pulmonary hypertension (PH) is a rare progressive disease characterized by
elevated pulmonary arterial pressure and increased pulmonary vascular
resistance which ultimately leads to right ventricular failure and premature
death (1). PH can be idiopathic, heritable or associated with multiple other
clinical conditions. However, the aetiology of PH is still incompletely
understood; multiple factors are involved in the pathogenesis of PH, including
genetic predisposition, thrombo-embolic, fibrotic and inflammatory mediators
(2-4).

The presenting symptoms of PH are nonspecific and therefore the diagnosis is
often delayed by on average 2 years (5). An early diagnosis is crucial as
without treatment PH has a median survival of 2.8 years and an estimated 5-year
survival of 34% (6). The definitive diagnosis can only be set after right heart
catheterization. Nevertheless, to monitor the patients* clinical condition less
invasive methods are preferred. Currently the six-minute walking test, NYHA
classification and echocardiography, all diagnostic tests which have proven to
correlate with disease severity and prognosis (7), are used to evaluate the
clinical condition of the patient. However, these diagnostic tools have
significant limitations and fail to identify early changes in cardiac
function.
Because of the frequent delay in diagnosis and limitations of current
diagnostic tools, there is a great need to identify additional measures. These
new measures, like biomarkers, can be combined with existing tools to detect
and monitor subtle molecular changes in the heart and lungs that reflect and
possibly prelude early deteriorations in cardiac function before they become
clinically visible. Currently, biomarkers play a role in management of patients
with heart failure from other origins like ischemic and hypertrophic heart
disease, but the specific role of biomarker measurement in diagnosing and
monitoring patients with pulmonary hypertension and associated right
ventricular failure has not been investigated yet.

Small biomarker studies have shown that well-established biomarkers for
acquired heart failure like BNP and NT-proBNP may also be relevant for various
classes of PH (8-9). However, the role of natriuretic peptides in monitoring
these patients longitudinally and in predicting outcome remains unclear.
Another hormone, endothelin-1, is elevated in the plasma of PH patients and
correlates with pulmonary arterial pressure (10). The marker for cardiac
necrosis, troponin T, is assumed to be associated with a poor prognosis for
patients with pulmonary arterial hypertension (PAH) (11).

In patients with acquired heart failure there is evident involvement of the
immunologic system, where cytokines contribute to sustained myocardial
dysfunction. The same phenomenon is described in PH patients. The exact pathway
to higher circulating cytokines is not exactly known. The intramyocardial
cytokine synthesis is probably brought up by increased wall stress and hypoxia.
Pro-inflammatory cytokine IL-6 is related to disease severity in idiopathic PAH
patients (12).

Despite recent improvements in medical treatment options, inevitable
complications as right heart failure and eventually premature death are a major
concern in patient with PH. Heart failure appears to result not only from
cardiac overload but also from a complex interplay among genetic,
neurohormonal, inflammatory and biochemical changes acting on the cardiac
myocytes, the
cardiac interstitium or both(13).

Therefore, the main goal of this project is to evaluate trends in biomarkers
and their relation with decreased ventricular function in adult patients with
pulmonary hypertension.
Thereby, this proposal aims to identify and validate new, potentially important
biomarkers, which can be implemented in the clinical management of patients
with PH. Finally, the goal is to establish the role of biomarkers as a clinical
tool for decision-making and outcome prediction.

The aim of this project is to evaluate the clinical value of biomarkers in
adult patients with pulmonary hypertension, in particular:
1) To quantify biomarkers of neurohormonal activity as NTproBNP, endotheline-1
and of immunological activity as CRP, IL-1, IL-6 and cardiac necrosis (troponin
T) in blood samples, using high density antibody arrays and ELISAs, obtained in
approximately 100 adult patients with pulmonary hypertension.
2) To asses the actual cardiac function (dimensions and function of the right
and left ventricle, measured with echocardiography) and the clinical condition
(measured with a 6-min walking test and NYHA classification) in these PH
patients.
3) To correlate circulating levels of identified biomarkers with cardiac and
systemic parameters.
4) To identify new biomarkers as a diagnostic and prognostic tool in patients
with PH.

By storing the blood samples of these pulmonary hypertension patients during a
period of 4 years, we will create a longitudinal database to study the
predictive value of biomarkers for mortality and morbidity. We expect new
biomarkers will be detected in the upcoming years, which can be studied then.

This will be a prospective and observational single center study.

not applicable