Genes Associated With Development of Pulmonary Arterial Hypertension in Patients With Congenital Shunt Lesions
Genes Associated With Development of Pulmonary Arterial Hypertension in Patients With Congenital Shunt Lesions
Pulmonary arterial hypertension (PAH) in patients with congenital heart disease (CHD) is
 associated with considerable morbidity and even mortality.

 Next to environmental risk factors, the investigators believe that there is an important role
 of genetic predisposition to develop PAH in CHD. There often is a discrepancy between the
 severity of PAH and the CHD, where it is useful to screen for PAH gene mutations. The
 investigators hypothesize that the genotype is partly responsible for the phenotypic
 variability in patients with congenital shunt lesions, where some develop PAH and others do
 not. If a genetic predisposition for PAH in CHD could be identified, then genetic screening
 could be a useful additional tool for early detection of patients at risk of pulmonary
 vascular disease and PAH development, with new opportunities for prevention or early
 treatment.
Pulmonary arterial hypertension (PAH) in patients with congenital heart disease (CHD) usually
 develops secondary to chronic volume overload of the pulmonary circulation following left to
 right shunt. This overload leads to elevated pulmonary artery pressure (PAP) and later to
 increased pulmonary vascular resistance. This causes pressure overload in the right heart,
 and thereby right ventricular and right atrial dysfunction, which may implicate considerable
 morbidity and even mortality.

 Since PAH nowadays is mostly detected when symptoms occur and PAP are elevated, the disease
 already evolved to an advanced (partially irreversible) stage and treatment is often
 initiated too late.

 Next to environmental risk factors, the investigators believe that there is an important role
 of genetic predisposition to develop PAH in CHD. In the past, certain genes have been
 identified that play a role in the development of atrial septal defect (ASD). There are also
 a lot of genes identified that play a role in PAH. Until now, not many research groups have
 studied a genetic link between CHD and PAH development. But it becomes more and more clear
 that there often is a discrepancy between the severity of PAH and the CHD, where it is useful
 to screen for PAH gene mutations. The investigators hypothesize that mutations in some of
 these known PAH genes or in other, still unidentified, genes are partly responsible for the
 phenotypic variability in patients with congenital shunt lesions, where some develop PAH and
 others do not. If a genetic predisposition for PAH in CHD could be identified, then genetic
 screening could be a useful additional tool for early detection of patients at risk of
 pulmonary vascular disease and PAH development, with new opportunities for prevention or
 early treatment.
Inclusion Criteria:

 -  Previous diagnosis of secundum atrial septal defect (ASD) or ventricular septal defect
 (VSD), with or without repair

 -  Development of PAH, defined as mean PAP ≥ 25 mmHg by right heart catheterization, in
 combination with a pulmonary wedge pressure of ≤ 15 mmHg and a PVR (pulmonary vascular
 resistance) of > 3 Wood units

 -  Preferably, families with congenital shunt lesions (at least three family members
 affected with ASD or VSD) will be considered for inclusion

 Exclusion Criteria:

 -  Other congenital heart disease

 -  Mental retardation

 -  Dysmorphic characteristics

 -  Chronic lung disease or total lung capacity < 80% of predicted value

 -  History of pulmonary embolism