Biomarker activity and chronic heart failure in adult patients with congenital heart disease.

Congenital heart disease (ConHD) with an incidence of around 8 cases per 1000
live births is the most prevalent form of congenital abnormality1. The number
of adults with congenital heart disease is steadily increasing due to the
success of paediatric cardiology and open-heart surgery. This nascent
demographic phenomenon is creating major issues concerning the optimal
management of adults with ConHD. It is estimated that now ± 30.000 adult
patients with ConHD are alive in the Netherlands. Total correction of
congenital heart disease is rare and most patients have residual lesions and
sequels 2-4. Observational studies in ConHD have taught us that at some point a
patient with a cardiac malformation will experience a decline in cardiac
function or complications 5.
Late complications such as heart failure, arrhythmias, residual lesions and
thromboembolic complications are common, and patients require pharmacological
treatment, reoperation, or catheter intervention. It is of great important to
deliver adequate interventions to patients with
ConHD and to detect complications as right and left ventricular dysfunction as
early as possible 6. Current clinical diagnostic tools such as echocardiography
and MRI fail to identify early changes that prelude adverse cardiac remodelling
and heart failure. Therefore, there is a great need to identify additional
measures that can be combined with existing tools to monitor subtle molecular
changes in the heart that reflect and possibly predict adverse changes before
they become clinically apparent. Currently biomarkers play a role in management
of patients with heart failure from other origin as ischemic and hypertrophic
heart disease, but the specific role of biomarker measurement in monitoring
patients with ConHD has not been investigated. Previous small studies of
biomarkers in ConHD patients have shown that well-established biomarkers for
acquired heart failure like NT-proBNP and BNP may also be relevant for ConHD
patients. However, the role of biomarkers in monitoring these patients
longitudinally and in predicting outcome remains unclear. Another measureable
hormone in ConHD patients is the vasoconstrictive peptide endothelin-1. High
levels of endothelin-1 are associated with worse NYHA class and more
ventricular impairment 7-9.
Also there is evident involvement of the immunologic system, where cytokines
contribute to sustained myocardial dysfunction in patients with acquired heart
failure. This phenomenon is also described in patients with ConHD. 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 cytokines IL-1 and IL-6 as well as
anti-inflammatory cytokines are elevated and especially more pronounced in the
cyanotic ConHD patients group 10-11.
Heart failure is a growing problem in patient with ConHD and it appears to
result not only from cardiac overload or injury but also from a complex
interplay among genetic, neurohormonal, inflammatory and biochemical changes
acting on the cardiac myocytes, the cardiac interstitium or both 12.
The main goal of this project is therefore to evaluate trends in biomarkers and
their relation with decreased functional capacity and ventricular function in
adult patients with ConHD. Thereby, this proposal aims to identify and validate
new potentially important biomarkers, which can be implemented in the clinical
management of patients with ConHD. 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 congenital heart disease, in particular:
1) 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
602 adult patients with ConHD.
2) assess the actual cardiac function (dimensions and function of the right and
left ventricle,
measured with echocardiography and/or MRI and the clinical condition measured
with an
extensive exercise protocol or NYHA classification) in these patients
3) correlate circulating levels of identified biomarkers with cardiac and
systemic parameters.
4) identify potential new biomarkers as diagnostic and prognostic tools.
5) repeat measurements of these biomarkers every year for 4 years, once after 8
to 10 years and follow the patient for 15 years.

By storing the blood samples of these well-defined ConHD patients, who will be
followed for 15 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 coming years, which can be studied then.
Additional financial resources will be sought for future studies.

This will be a prospective and observational single-center study.

Not applicable