Congenital heart disease is the most common congenital malformation and accounts for about eight cases per 1,000 births.1 Due to tremendous developments in cardiac surgery, nearly 90% of all children with congenital heart disease reach adult age. In patients with congenital heart disease, pulmonary arterial hypertension (PAH) may develop due to increased pulmonary arterial flow as a result of a left-to-right shunt. PAH may lead to a decreased functional capacity and right ventricular failure, and is often associated with early death. The Eisenmenger syndrome is an extremely serious form of PAH, characterised by severe irreversible PAH and reversal of the shunt, leading to cyanosis initially during exercise and, at a later stage, at rest. The Eisenmenger syndrome involves about 1% of all patients with congenital heart disease.2 In this article we will summarise the current state of PAH associated with congenital heart disease and the Eisenmenger syndrome.
Development of Pulmonary Arterial Hypertension
PAH is defined as an elevated mean pulmonary arterial pressure of >25mmHg at rest or 30mmHg during exercise, measured during right heart catheterisation.3 The development of PAH is usually the result of excessive pulmonary blood flow due to a left-to-right shunt and is related to the size, type and dimensions of the defect and the correction status.2,4,5 Chronic exposure of the pulmonary vasculature to increased blood flow may induce vasoconstriction and structural changes, i.e. intimal fibrosis, medial hypertrophy and increased production of extracellular matrix in the adventitia. The structural changes result in increased pulmonary vascular resistance and PAH. These changes may ultimately lead to a reversal of the systemic-to-pulmonary shunt accompanied by cyanosis, the so-called Eisenmenger syndrome.6 A magnetic resonance image (MRI) of a patient with Eisenmenger syndrome is shown in Figure 1.
Various congenital heart defects may lead to PAH or Eisenmenger syndrome, such as univentricular heart, truncus arteriosus, patent ductus arteriosus, septal defects or surgical shunts, i.e. Potts, Waterston and Blalock-Taussig shunts.7 By far the largest proportion of patients with PAH have a septal defect, such as ventricular septal defect, primum or secundum atrial septal defect or complete atrioventricular septal defect.7 Early closure of the defect may prevent the subsequent development of PAH.8
Epidemiology
Until recently, the prevalence of PAH in patients with congenital heart disease was not known. Two databases on adult congenital heart disease have been analysed recently regarding the prevalence of PAH among these patients. The CONgenital COR vitia (CONCOR) registry is a nationwide registry of adult patients with congenital heart disease in The Netherlands that was designed to study the epidemiology and the late outcome of congenital heart disease, and includes adult patients with structural congenital heart disease from both referral and regional hospitals.9 Data analysed from the CONCOR registry showed a prevalence of PAH of 4.2% (n=248) among all 5,970 registered adult patients. Of 1,824 patients with a septal defect in the registry, 6.1% (n=112) had PAH. Among the 899 patients with a previously closed septal defect, 3.3% (n=30) had PAH. The Eisenmenger syndrome involved about 1.1% of all patients with congenital heart disease.2
A higher prevalence of PAH was found in the Euro Heart Survey (EHS), where PAH was present in 531 of 1,877 of patients (28%). However, this survey contained data only from adult patients with one of eight selected congenital heart defects from 26 countries and 79 centres (61% tertiary centres) throughout Europe.10 In the EHS, PAH was unexpectedly common, which was probably due to the large number of patients who attended a referral centre (83%) or who were referred for closure of the defect (35%).7 In summary, data from these two large databases indicate that PAH is a risk factor in the long-term clinical course of septal defects with a prevalence of at least 6%.
Ventricular septal defect is the most frequent underlying defect (42%) among patients with PAH in the CONCOR registry. The median age of the CONCOR patients with PAH is 38 years (range 18–81 years), and 60% of them are women.2 PAH increases with age and is associated with a worse functional class and greater risk of death, particularly among patients with Eisenmenger syndrome.7
Clinical Presentation
Clinical signs of PAH are variable and depend on the underlying congenital heart disease, patient age, repair status and degree and direction of shunting. Symptoms are related to reduced cardiac output, congestive heart failure, arrhythmias and hypoxaemia and may affect quality of life, morbidity and mortality.
General symptoms suggestive of PAH are non-specific and may include dyspnoea, chest pain, peripheral oedema and syncope.3 In patients with Eisenmenger syndrome, central cyanosis and clubbing are the most visible clinical consequences. However, it should be emphasised that not all Eisenmenger patients are cyanotic at rest.
In cyanotic patients, compensatory mechanisms to maintain adequate tissue oxygenation take place. Chronic cyanosis results in elevated renal production of erythropoietin, thus promoting erythropoiesis and secondary erythrocytosis.11 Repeated phlebotomies in cyanotic patients with congenital heart disease and PAH induced iron deficiency and should be abandoned. Iron deficiency has been associated with an increased risk of cerebrovascular events in cyanotic adults.12 Phlebotomy is indicated only for symptomatic hyperviscosity syndrome and should be performed with simultaneous isovolumic fluid replacement to avoid a catastrophic collapse. In patients with Eisenmenger syndrome one or more of the following non-cardiac complications may occur: bleeding, thrombotic diathesis, endocarditis or cerebral abscess and impaired hepatic and renal function.13 Therefore, Eisenmenger syndrome can be considered as a multisystem disorder.
Prognosis
In patients with Eisenmenger syndrome, mortality is high: 21% died during the five-year follow-up period of the EHS.7 The general prognosis is related to both the severity of PAH and the underlying congenital heart disease. Variables associated with poor long-term outcome are syncope, elevated right heart filling pressure, severe hypoxaemia and Down‘s syndrome.4,14 PAH is a progressive condition and patients usually die between the third and fifth decade of life. In patients with Eisenmenger syndrome, median survival is reduced by approximately 20 years compared with healthy individuals.13 Around 55–63% of patients with Eisenmenger syndrome die of sudden cardiac death. Other frequent causes of death include congestive heart failure, haemoptysis, brain abscess, thromboembolism and complications of pregnancy or non-cardiac surgery.15,16 However, survival in patients with Eisenmenger syndrome is far better than the median survival of 2.8 years in patients with idiopathic pulmonary arterial hypertension.17,18
New Developments in Medical Treatment Strategies
Once the Eisenmenger syndrome is present, surgical closure of the defect is no longer an option. The right ventricle will be unable to generate enough pressure to overcome the high pulmonary vascular resistance and will decompensate. Until recently, treatment options for patients with PAH associated with congenital heart disease were limited to the avoidance and treatment of complications. As natural survival prospects are far better compared with idiopathic or other forms of PAH, heart–lung transplantation is restricted to highly symptomatic patients and those in whom life expectancy is considered short.
In the last decade, new medical treatment strategies have been demonstrated to be beneficial in patients with PAH.18–20 Recent studies have shown short-term positive treatment effects of intravenous prostacyclin, endothelin receptor antagonist and phosphodiesterase-5 (PDE5) inhibitors in patients with PAH associated with congenital heart disease.20–29 The different pathways for this medical treatment of PAH are shown in Figure 2. Prostacyclin, or epoprostenol, is a potent short-acting vasodilator and inhibitor of platelet aggregation produced by the vascular endothelium. In patients with PAH, the synthesis of prostacyclin is markedly diminished in the pulmonary endothelium. However, prostacyclin therapy is complicated by the need for continuous intravenous infusion or frequent nebulisers.21 Bosentan inhibits the endothelin A and B receptors and competes with endothelin-1, which usually binds to those receptors. Endothelin-1 is a potent vasoconstrictor and a mitogen for vascular smooth-muscle cells and fibroblasts. Overexpression of endothelin-1 has been demonstrated in the pulmonary vasculature of patients with PAH. By blocking endothelin receptors type A and B, bosentan may decrease endothelin-related vasoconstriction and smooth cell proliferation and thus modify functional and structural changes in the pulmonary vessels. PDE5 is abundantly expressed in the lung, where it inactivates cyclic guanosine monophosphate (cGMP), thereby inhibiting the vasodilatory effects of nitric oxide and atrial natriuretic peptides. The PDE5 inhibitor sildenafil causes relaxation of pulmonary vascular smooth muscles by activating large-conductance, calcium-activated potassium channels.30
New medical treatment strategies are promising; however, experience in adults with congenital heart disease is limited and no long-term survival benefits following new medical treatment strategies have yet been demonstrated. Despite therapy, the condition may deteriorate. In such situations combination therapy may improve outcome in patients with PAH. However, studies to assess the effect of combination treatments are lacking.
Perspective
Surgical correction of the underlying congenital heart defect during childhood, before the characteristic changes in the pulmonary arteries have started to appear, will mostly prevent the development of PAH and its severe form, Eisenmenger syndrome.31,32 Due to improved diagnostic and treatment strategies, the prevalence of PAH could be expected to decline. However, the increased prevalence of PAH with age makes a strong decline in PAH prevalence unlikely. Improved understanding of the underlying pathophysiological mechanisms, careful medical management and the introduction of new medical treatment strategies are bound to improve quality of life and long-term survival prospects for patients with PAH and congenital heart disease.