Pulmonary hypertension (PH) is defined as increased median pressure in the pulmonary artery above 25 mmHg. The definition of pulmonary arterial hypertension (PAH) includes, in addition to PH, pulmonary capillary pressure lower than 15 mmHg and pulmonary vascular resistance (PVR) higher than 3 Wood units. These definitions do not include the possibility of PH occurring during heart load. (1)

Pulmonary hypertension is a chronic, progressive disease which is the result of the damage of the pulmonary arterial endothelium, causing release of the mediators that stimulate the multiplication and migration of smooth muscle cells, which in turn causes gradual obliteration of the arterial lumen. (2) The incidence of PAH in patients with adult congenital heart diseases (ACHD) is different in different registries, but it is usually around 6-11%. (3) The incidence increases with the age of the patient (CONOR registry). (4)

According to the conclusions of the latest global Pulmonary Hypertension Symposium in 2013, PAH in ACHD can be divided into four sub-groups (5):

Pulmonary vascular resistance (PVR), together with PAH, is very important in ACHD. Patients with a L-R shunt have a high pulmonary flow, can have high PAH and a still acceptable PVR, and surgical intervention is possible for these patients despite PAH. On the other hand, patients with a low pulmonary flow in Fontan circulation can develop PVR without PAH. (7)

There is a significant difference between PAH caused by congenital heart disease and idiopathic PAH; it has a more benign course in ACHD. This is caused firstly by the morphology of the right ventricle which adapts to the high pressure and later leads to heart failure. Although the pressures in the lungs are extremely high, shunts act as a “safety valve”, protecting the right ventricle, at the cost of cyanosis and limited exertion capacity, but the survival is significantly longer compared with PAH of a different etiology.

PAH treatment is limited. Supportive therapy includes oral anticoagulants, diuretics, oxygen therapy, in some cases digitalis, and when anemia needs to be treated, iron supplements. Calcium antagonists, although still recommended in guidelines, have not proven to be very effective in treating PAH. Targeted advanced therapy is the only one that has an effect on the clinical improvement and prolongation of life in patients with PAH, with reversibility tests not being crucial to the decision of implementing it.

Advanced therapy of PAH includes three types of medication which affect the reduction of vasoconstriction or stimulate vasodilation and have an anti-proliferative effect. These are (8):

Prostacyclin derivatives are powerful vasodilators and smooth muscle cell proliferation inhibitors, and affect the activity of thromboxane A2. They are administered intravenously or through inhalation. Their positive effect on hemodynamics and PAH symptoms has been proven, but they are unsuitable for long-term use due to toxicity and side effects. Today they are most widely used as the “third line” in case of deterioration together with other advanced medication, and prior to heart and lungs transplantation. (9)

Nitrous oxide (NO) is a powerful vasodilator and thrombocyte and smooth muscle cell proliferation inhibitor. In PAH, NO production is significantly decreased, which causes vasoconstriction and cell proliferation. By preventing cyclic guanosine monophosphate (cGMP) activation, phosphodiesterase inhibitors (PDE-5) stimulate vasodilation and reduce smooth muscle cell proliferation. In all studies and registries, sildenafil had a positive effect on quality of life, especially on the improvement of the 6-minute walk test. Other PDE-5 inhibitors had a similar effect. Today they are most often used when endothelin receptor antagonists are ineffective or in a combination with them in case of disease progression, but can be administered as the first medication for PAH in ACHD. (10)

Endothelin receptor antagonists are the newest medication for the treatment of PAH in ACHD. Their effectiveness is based on publications that have established that endothelin values are significantly higher in patients with CHD-PAH, and that their values increase significantly between the right ventricle and the pulmonary veins, i.e. in pulmonary circulation. (11) The first medication from this group, bosentan, has proven to be effective in small series or registries, which has made randomized studies possible. (12) The outcomes of these studies have made these medications the first choice for treatment of PAH in ACHD.

Eisenmenger’s Syndrome (ES) was named after the Austrian doctor who first described it in the late 19^th century, and its pathophysiology was defined and clinically described in detail by P. Wood in the mid-20^th century. This syndrome is defined by a severe pulmonary hypertension connected with congenital heart disease, i.e. a left-to-right shunt which has in time turned into right-to-left shunt and led to chronic cyanosis with an effect on multiple organ systems. It is clinically characterized by exertion intolerance, dyspnea, and cyanosis, and in the long term by arrhythmia and sudden death as well as heart failure and hemoptysis. Life expectancy for these patients is significantly reduced, and exertion tolerance is extremely low. Survival depends on the degree of cyanosis, exertion tolerance (usually determined through a 6-minute walk test), the degree of cardiac compensation, and the dynamics of the symptom progression. (13)

The decision to introduce advanced therapy is based on the 6-minute walk test score of less than 350 m and arterial O₂ saturation below 85%. New York Heart Association (NYHA) class is not crucial for the decision, but the most often included patients are those from NYHA III. (14) The first-choice medication, according to recommendations, is bosentan, while all the rest are second-line choices.

The first randomized study with BREATHE-5 bosentan was conducted on patients with ES. (15) It included stabile patients over the age of 12, in the third functional class, with a 6-minute walk test distance of 150-450 m. The study included 54 patients randomized 2:1 into groups receiving the medication and placebo. The primary aim was to study the changes in oxygen saturation in a resting as well as changes to PVR after 16-week treatment. The secondary aim included following changes in hemodynamic parameters, 6-minute walk tests, and functional class. The study results indicated that after 16 weeks of bosentan therapy, patients with ES show no decrease in oxygen saturation, their exertion tolerance in the 6-minute walk test is significantly improved (+53.1 m, P=0.008), and PVR is reduced (-472 dyn.sec.cm^-5, P=0.04), with satisfactory medication safety. Administration of the medication was continued for patients in the BREATHE-5 open-label extension study, and the results consistently indicated further improvements in the patients who continued with the medication, as well as significant improvement of the patients in the placebo group. (16) Medication safety was good. A slight and insignificant hemoglobin decrease was reported. More serious side effects reported include a 10% increase of transaminase, so monitoring is required during treatment, which should be terminated in case the increase was >8-fold or if there are clinical signs of liver insufficiency.

Treatment duration quickly became an important question. The results from the registries monitoring patients undergoing bosentan therapy are cause for optimism. Long-term bosentan treatment over a period of 6 years achieved a significant decrease in the values of pro brain-type natriuretic peptide (proBNP) and a significant mortality reduction (17) and the existing improvements in the 6-minute walk test as well as improvement of the functional class over the 8-year monitoring period remain constant, with a slight further improvement for some of the patients. (17, 18)

The decision to close the shunt is based on estimating whether the surgical intervention will prevent PAH progression, improve long-term prognosis, or improve symptoms. Once a significant PVR is established, surgical intervention can be risky. Patients with a PVR up to <4 Wood/m² are considered to be operable, and those with >8 Wood/m² inoperable. An individual assessment at a tertiary center is required in the case of PVR of 4-8 Wood/m².

There is no clear proof that advanced therapy helps patients with PVR become eligible for corrective surgical intervention, but it can be conducted individually.

This condition is treated like idiopathic PAH.

In these cases the patient has undergone CHD correction, but the PAH is still present or can continue to increase despite total correction; for some patients it is increased due to residual defects or as a side effect of an earlier surgical intervention. Endothelin receptor inhibitors, primarily macitentan, are the first line of advanced therapy for those patients.

Macitentan, a double endothelin inhibitor, was proven effective in the SERAPHIN study (19) whose primary goal was to monitor “time to disease progression”. This term is increasingly used in other, later studies among patients with ACHD, but it must be clearly defined. In the SERAPHIN study it related to the time of appearance of one of the following events: death, atrial septostomy, lung transplant, introduction of prostanoids, and other signs of disease deterioration.

The secondary aim of the study was monitoring of the changes in the 6-minute walk test, functional class, cause of death, and, understandably, the safety of the treatment during the 6-month monitoring. The results of the study showed that macitentan significantly reduces the risk of morbidity and mortality: 45% RR (P< 0.0001) for a 10 mg per day dose, and 30% RR (P=0.0108) for a 3 mg dose. (19) Macitentan was particularly effective in patients who had not previously undergone advanced therapy as compared to placebo patients (a 37 m increase of walk distance for the 6-minute walk test for the group taking 10 mg dose per day, P<0.01). It is interesting to note that patients with worse functional class (III/IV) improved much more as a result of the treatment.

Combined advanced therapy with both bosentan and sildenafil was tested on patients with PAH and ACHD. The monitored parameters were the 6-minute walk test and PVR. Patients receiving bosentan therapy and the combined bosentan and sildenafil therapy showed significant improvement when compared to placebo, but the combined therapy showed no statistically significant difference compared with bosentan monotherapy. (20) Introducing the second (phosphodiesterase inhibitors) or third line (prostacyclin) of advanced therapy is recommended in case of further disease deterioration.

Patients with Fontan circulation are characterized by the absence of the sub-pulmonary ventricle. Due to this, increased PVR significantly effects the hemodynamic fall (“falling Fontan”), since the flow in the arterioles adversely affects the maintenance of the pulmonary flow. (21)

The reason for increased PVR despite PAH absence is probably the combination of the lung flow prior to the operation, i.e. postoperative non-pulsatile blood flow that likely affects the decreased stimulation to the creation of microcirculation, production of NO and prostacyclin disruption, and negative remodeling and endothelium dysfunction. (22) Introducing advanced therapy on patients with Fontan circulation is based on administering of prostaglandin (iloprost) to a group of patients with significant hemodynamic deterioration, which achieved improvement of the maximum oxygen consumption (+1.3 ml/kg/min, P=0.04) within that group of patients. (23)

Currently a study (TEMPO) is under way which tests the administering of bosentan to stable patients with Fontan circulation, monitoring the effect of the medication on the physical exertion, hemodynamics, and changes to the functional class. (24)

Treatment of pulmonary arterial hypertension has been significantly improved by the introduction of new medication, which affect the reduction of vasoconstriction or stimulate vasodilation in pulmonary circulation and which have an anti-proliferative effect. Around one tenth of the patients with ACHD develop PAH, and advanced therapy that can be administered long-term has a significant effect on clinical improvement (functional NYHA class decrease, increase in walking distance) while also prolonging life expectancy.