Surgical repair of tetralogy of Fallot with pulmonary atresia and major aortopulmonary collaterals consists of unifocalisation of collaterals to the pulmonary arteries and the use of a conduit from the right ventricle to the pulmonary arteries with or without ventricular septal defect closure.Reference Malhotra and Hanley 1 Repair may be complicated by segmental pulmonary arterial hypertension, whereas in some patients, pulmonary blood flow remains provided by aortopulmonary collaterals or surgical aortopulmonary shunts. Patient condition may deteriorate over time with worsening segmental pulmonary arterial hypertension, gradual narrowing and obstruction of collaterals, increasing cyanosis, and heart failure.
Pulmonary vasodilators have been shown to provide short- and longReference Gatzoulis, Beghetti and Galie 2 -term benefits in pulmonary arterial hypertension associated with CHD and Eisenmenger syndrome with a few small studies carried out on tetralogy of Fallot with pulmonary atresia and major aortopulmonary collaterals and segmental pulmonary arterial hypertension with or without repair.Reference Grant and Berger 3 – Reference Yasuhara and Yamagishi 7 This paper reports use of pulmonary vasodilators in three patients and describes the limited existing literature for this diagnosis.
Case reports
Patient 1, a 26-year-old housewife with no previous intervention presented in NYHA Class II and deteriorated after 2 years to class III with increased cyanosis, very poor exercise tolerance and inability to perform her household work. On angiography, the central pulmonary arteries were found to be severely hypoplastic and all the catheterised collaterals had systemic pressures. The patient was started on bosentan at 29 years of age, as soon as oral pulmonary vasodilators became available, and she quickly improved to NYHA class II, being able to keep up with all her household work and outside activity with reasonable measured maximal and submaximal exercise tolerance and quality of life without deterioration over 14 years (Table 1).
Table 1 Functional class, oxygen saturation and exercise data.
O2 sat=oxygen saturation; VO2 max=maximal oxygen consumption; 6MWD=6-minute walking distance
Patient 2, a 21-year-old male with a left Blalock–Taussig shunt presented in NYHA Class III with stable cyanosis but with very poor exercise tolerance. On angiography, the left upper lobe and right lung collaterals were found to have systemic pressures, whereas the left lower lobe collateral had normal pressures (Fig 1a–d). He was treated with bosentan, improved to NYHA class II with reasonable reclamation of home and outside activity and a good quality of life, and remained stable throughout 10 years (Table 1).
Figure 1 Anatomy of Patient 2 from angiography. ( a ) Right upper lobe collateral without stenosis. ( b ) Left upper lobe collateral without stenosis. ( c ) Left lower lobe collateral with severe stenosis, indicated with an arrow. ( d ) Peripheral injection in the low-pressure segment of the left lower lobe collateral.
Patient 3, a 31-year-old female with left and right Blalock–Taussig shunts, presented in NYHA Class IV with severe cyanosis and an oxygen saturation of 52% on room air. She was wheelchair-bound, on continuous oxygen therapy, and unable to perform outside activity. On angiography, the central pulmonary arteries were found to be severely hypoplastic with minimal contrast flow in the collaterals. She received bosentan therapy and quickly improved to NYHA class II, got off oxygen therapy, moved out of her parents’ house, and presently has a good quality of life without deterioration observed over 2.5 years (Table 1).
All patients had stable haemoglobin and liver-function test findings without adverse events or deterioration throughout the follow-up investigation. Maximal and submaximal exercise tolerance remained low, possibly due to cyanosis, but all patients reported significant, sustained improvement, with the NYHA class IV patient exhibiting the most pronounced effect.
Discussion
Aortopulmonary collaterals in tetralogy of Fallot with pulmonary atresia and hypoplastic pulmonary arteries provide blood flow to various or all lung segments, their numbers correlating with the severity of abnormalities of the pulmonary arteries.Reference Shimazaki, Maehara, Blackstone, Kirklin and Bargeron 8 Aortopulmonary collaterals arise from the remnants of the intersegmental arteries in about 40% of patients with tetralogy of Fallot with pulmonary atresia, in whom regression of the 6th pharyngeal arch arteries results in abnormal development of the pulmonary arteries and the arterial duct.Reference Yasuhara and Yamagishi 7 Aortopulmonary collaterals develop progressive stenosis and occlusion or pulmonary arterial hypertension in segments supplied by non-stenotic collaterals with systemic pressures.
Surgical intervention with unifocalisation followed by complete repair either in one or multiple stagesReference Malhotra and Hanley 1 yields satisfactory results in many patients but may be challenging in cases complicated by diminutive pulmonary arteries or elevated pulmonary pressures; moreover, multiple staged surgeries in patients with good-sized pulmonary arteries, who may remain physically limited but stable for many decades, may be associated with an increased risk compared with that from conservative management.Reference Bull, Somerville, Ty and Spiegelhalter 9 Heart–lung transplantation presents several issues in this population due to donor shortage, previous surgeries, unavailability of programmes accepting patients with complex CHD, and guarded long-term results, whereas the older age of these patients at clinical deterioration often renders them poor candidates for transplantation.Reference Grady, Gandhi, Sweet, Mao and Huddleston 10
Pulmonary arterial hypertension in this diagnosis may be due to increased pulmonary blood flow through non-stenotic collaterals or systemic-to-pulmonary shunts, hypoplastic and/or segmentally unequal pulmonary arterial beds, vascular spasm, and peripheral pulmonary stenosis.Reference Yasuhara and Yamagishi 7 Histologic analysis of collaterals has shown medial hypertrophy and intimal proliferation similar to the pulmonary vascular remodelling observed in idiopathic pulmonary arterial hypertension.Reference Schermuly, Pullamsetti and Kwapiszewska 11
There are only five similar small studies in the literature. Pulmonary vasodilators improved activity, as well as echocardiographic and haemodynamic variables in eight children after right ventricle to pulmonary artery conduit with or without residual ventricular septal defect.Reference Grant and Berger 3 Bosentan induced haemodynamic improvement in two children after complete repair,Reference Yamamura, Nagata, Ikeda, Ihara and Hara 6 and increased 6-minute walking distance without clinical change in seven adult patients, only two of whom had major collaterals.Reference Schuuring, Bouma and Cordina 5 In a study using sildenafil in five adult patients, three of whom had right ventricle to pulmonary artery conduit with or without residual ventricular septal defect, four improved but one did not tolerate therapy.Reference Lim, Vettukattill, Salmon and Veldtman 4 Pulmonary vasodilator therapy in two adult patients without repair and in 1 child with repair showed a benefit in two patients but deterioration in one patient, leading to treatment discontinuation.Reference Yasuhara and Yamagishi 7 In summary, each study had two to eight children and adult patients, who had usually undergone right ventricle to pulmonary artery conduit, with mostly positive response, but with an adverse effect observed in two patients possibly due to ventilation-perfusion mismatch or volume overload.Reference Yasuhara and Yamagishi 7 The follow-up period was mostly 2–3 years, and this follow-up investigation was carried out only in two patients in all the studies over 6 years.
Given the rarity of the diagnosis, our study is a small series, reporting the beneficial effect of endothelin antagonism on three adult patients without repair, with consistent and long lasting clinical improvement observed without significant change in exercise tolerance. Even in idiopathic pulmonary arterial hypertension, study endpoints have gradually moved from exercise tolerance to more solid mortality and delayed-worsening endpoints.Reference Savarese, Paolillo and Costanzo 12 The advantages of this study compared with previous reports are the homogeneity of the population, comprising patients not having undergone repair and having a different physiology, and the significantly longer follow-up period of 2.5–14 years without observing any adverse events or the expected clinical deterioration. These facts may be crucial in such severely ill patients with very limited options, especially in the absence of a heart–lung transplantation possibility.
Pulmonary vasodilators probably work in tetralogy of Fallot with pulmonary atresia and major aortopulmonary collaterals by reversing pulmonary vascular remodelling, and if that is the treatment target, early pulmonary vasodilator treatment before onset of segmental pulmonary arterial hypertension may provide greater sustained response, similarly to idiopathic pulmonary arterial hypertension. On the other hand, early vasodilation of aortopulmonary collaterals may aggravate pulmonary vascular disease in some lung segments, whereas some patients do not respond favourably, making general recommendations impossible.
Acknowledgements
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This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
Conflicts of Interest
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Ethical Standards
This work does not involve human and/or animal experimentation.
