Pulmonary hypertension in surgically-corrected congenital heart disease. Is it predictable?

1 - Generalities

Congenital heart diseases (CHD) occur in nearly 1% of live births, and pulmonary artery hypertension (PAH) is a major complication in children with systemic-to-pulmonary shunts. Approximately 5% of adults with CHD will develop PAH. Among adults with PAH, 11.3% have PAH that is CHD-related (they are PAH-CHD related patients, but in the paediatric age, 50% of all cases of PAH have underlying CHD or Eisenmenger physiology.
In CHD at high risk of PAH, early surgical correction is desirable in order to avoid irreversible damage to pulmonary vessels, however in some cases, diagnosis can be late and surgical and/or medical management not easy. Generally, surgical correction of CHD in presence of PAH is suitable when pulmonary vascular resistance (PVR) is less than 6 Wood Units (WU) with values between 6 and 10 WU represent a grey zone. On the other hand, presence of bi-directional or right-to-left shunt is considered a contraindication to surgical intervention. However, PAH progression after surgical repair can be unpredictable, irrespective of age at correction and PVR at closure.
We report two cases of surgically-corrected CHD patients who developed severely symptomatic PAH 20 years after surgical correction.

2 - Clinical examples

Case n.1: G.I., female. Neonatal diagnosis of transposition of the great arteries with ventricular septal defect. At 3 months, surgical pulmonary artery banding and atrial septectomy is performed. At 15 months, cardiac catheterisation shows: effective pulmonary artery banding, mean pulmonary artery pressure of 25 mmHg. One year later surgical correction is carried out: atrial and ventricular septum are closed with a patch, arterial switch is performed and pulmonary trunk is enlarged. Post-operative course is regular. Post-operative echo shows a residual ventricular septal defect with a trivial residual shunt. No pulmonary artery branches stenosis occur. When she is 10 years old, echocardiography shows a mild pulmonary artery pressure rising (estimated systolic pressure 40 mmHg). Two years later, a cardiac catheterisation shows a moderate pre-capillary pulmonary hypertension (pulmonary wedge 11 mmHg, mean pulmonary pressure 35 mmHg, systolic pulmonary pressure 50 mmHg). In the next years symptoms such as effort dyspnoea and syncope appear, such that when she is 21 y.o. a new catheterisation is performed, showing severe PAH (RV/LV ratio 0.8, mean PAP 70 mmHg, wedge pressure 12 mmHg), severely impaired cardiac output (1,3 L/min/m2), non- significant interventricular residual shunt (QP/QS 1.2), no evidence of previous pulmonary embolism. No vasculitis are detected. A therapy using Bosentan and diuretics is started.

Case n.2: P.P., female. When she is 4 y.o. a large ventricular septal defect (VSD) is found, after catheterisation (showing moderate PAH, RV/LV ratio 1.0, reduced PVR after vaso-reactivity test using pO2 100%), surgical correction is indicated. Post operative course is regular, with stable moderate pulmonary hypertension. She becomes pregnant twice: the pregnancy is successfully completed; on the other hand the second one is complicated by uterine atony and massive uterine hemorrhage. Because of worsening dyspnoea, cardiac catheterisation is performed. It shows a trivial residual VSD shunt (QP/QS 1.1), near systemic RV pressure (RV/LV ratio 0.9, mean PAP 75 mmHg), normal pulmonary wedge pressure (10 mmHg), normal cardiac output (QS 2.8 L/min/mq and a negative vasoreactivity test (QP/QS 1.1, RV/LV ratio 0.75, mean PAP 65 mmHg, QS 4.8 L/min/mq, pulmonary wedge 10 mmHg). Therapy with Bosentan is started.

3 - Prognosis

Pulmonary arterial hypertension has a poor prognosis in congenital heart disease patients. Ischemic and embolic events, bleeding, infection and cerebral abscesses, progressive right ventricular failure, cardiac arrhythmia and sudden cardiac death are common in these patients (1).
However, long term outcome of PAH-CHD patients is better than in idiopathic-PAH patients because of their preserved systemic cardiac output by right to left shunt. The main challenge for the cardiologist and the surgeon in PAH-CHD patients is to choose the most appropriate treatment at the time of diagnosis for a given patient.

4 - Treatment

Clinical classification distinguishes four types of PAH-CHD:  A) Eisenmenger syndrome, 
B) significant shunt lesions with severe PAH (no shunt reversal and no cyanosis), C) small defects with PAH (clinical picture similar to IPAH), and D) PAH after repair of CHD (2). CHD complexity, shunt type and dimensions, co-morbidity and genetic syndromes are all parameters that will influence outcome. Invasive pre-operatory pulmonary artery pressure and resistance measurement through right heart catheterisation play a central role in decision-making regarding these patients: PAH-CHD patients with pulmonary vascular resistance (PVR) <6 wood units (WU) are generally considered good candidates for surgical correction. Patients with PVR between 6 and 10 WU may be considered for surgical correction. In patients with higher PVR or right to left shunt (Eisenmenger syndrome) surgery is in fact, contra-indicated.

5 - Case Discussion

However, genetic predisposition can influence PAH progression even after surgical correction or in presence of mild left-to-right shunt (groups C: patients with small defects with PAH and D: PAH after repair of CHD).
The two above-reported cases are emblematic of this issue. Case n.1 was pulmonary-bended at 3 months and corrected at two years, in presence of upper-limit of the normal PA pressure and normal PVR. However, despite surgical correction, PAH progressively worsened. Case n. 2 was corrected late, with moderate PAH that was stable until the second pregnancy.
Assessment of pulmonary vascular bed involvement before surgery plays a central role in clinical management, allowing to choose between exclusively medical, surgical or medical and surgical options. In particular, when appropriate, medical therapy can be started 2-3 months before surgical closure or immediately post surgery in order to avoid a PAH crisis, that is conditioned by high mortality (about 20%). On the other hand special surgical techniques for PAH patients are available, such as flap valve ventricular septal defect patch or fenestrated atrial or ventricular septal patches and devices. However, more data are needed to determine the long-term benefits and risks of these approaches.
Lastly, medical treatment is useful in PAH-CHD patients. ESC guidelines for PAH indicate treatment with Bosentan (I A), other Endothelin receptor anthagonists (IIa C) and phosphodiesterase type-5 inhibitors (IIa C), or prostanoids (IIaC) in patients with PAH-CHD patients or Eisenmenger’s syndrome. Combination therapy may be considered in patients with Eisenmenger’s syndrome (IIb C) as second step therapy (5).