International Journal of Cardiology 177 (2014) 340–347

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Review

Pulmonary arterial hypertension associated with congenital heart disease: Recent advances and future directions Michael A. Gatzoulis a,⁎, Maurice Beghetti b, Michael J. Landzberg c, Nazzareno Galiè d a

NIHR Cardiovascular BRU, Royal Brompton Hospital and the National Heart and Lung Institute, Imperial College, London, UK Children's Hospital, University of Geneva, Geneva, Switzerland BACH Pulmonary Hypertension Service, Departments of Paediatrics, Medicine and Surgery, Boston, USA d Department of Experimental, Diagnostic and Specialty Medicine—DIMES, Bologna University Hospital, Bologna, Italy b c

a r t i c l e

i n f o

Article history: Received 14 July 2014 Accepted 16 September 2014 Available online 28 September 2014 Keywords: Congenital heart disease Pulmonary arterial hypertension Eisenmenger syndrome Left-to-right shunts Fontan circulation

a b s t r a c t Congenital heart disease (CHD), the most common inborn defect, affects approximately 1% of all newborns worldwide. Advances in its diagnosis and treatment have led to a dramatic improvement in patients' quality of life and long-term survival prospects. However, recently it has been realised that many of these patients are affected by ongoing and life-long cardiac issues, namely residual and progressive haemodynamic lesions, arrhythmia and sudden cardiac death, as well as the development of chronic heart failure and pulmonary arterial hypertension (PAH) — all of which merit tertiary care. Unfortunately, many patients with CHD are lost to followup, due to the assumption that their initial response to surgical and or catheter intervention in childhood led to cure. Furthermore, there are many patients with undiagnosed or unoperated CHD in the developing world coming to medical attention during adulthood. Our article focuses on advances in the management of PAH associated with CHD, a common association with an adverse impact on quality of life and survival prospects that affects approximately 10% of patients with CHD. Much of the recent progress in PAH–CHD has focused on the extreme end of the disease spectrum, namely on Eisenmenger syndrome. Herein we discuss this progress and future directions for this emerging cardiovascular field. © 2014 Elsevier Ireland Ltd. All rights reserved.

1 . Introduction Pulmonary arterial hypertension (PAH), defined as a pulmonary arterial pressure of ≥25 mm Hg at rest in the presence of normal pulmonary capillary wedge pressure (i.e. ≤15 mm Hg), is relatively common amongst patients with congenital heart disease (CHD) [1]. Recent prevalence data on PAH in adult CHD patients report rates between 4.2% (in a national CHD registry [2]) and 28% (in a cohort of tertiary European CHD centres) [3]. Although the exact prevalence of PAH in association with CHD (PAH–CHD) in the community remains unknown, many patients with CHD have sadly been lost to specialist follow-up [4]. Furthermore, severity of PAH and its rate of progression often remain largely unknown, even amongst patients with CHD who are currently under specialist cardiac care. This lack of information occurs because the urgency to prevent the development of PAH in infancy and early childhood in the developed world at least tends to relax once the diagnosis is made and early surgery or catheter intervention is performed. However, a proportion of patients who have received

⁎ Corresponding author at: Adult Congenital Heart Centre and National Centre for Pulmonary Hypertension, NIHR Cardiovascular BRU, Royal Brompton Hospital and the National Heart and Lung Institute, Imperial College, Sydney Street, London SW3 6NP, UK. Tel.: +44 207 351 8602; fax: +44 207 351 8367. E-mail address: [email protected] (M.A. Gatzoulis).

http://dx.doi.org/10.1016/j.ijcard.2014.09.024 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

seemingly appropriate childhood therapy go on to develop late PAH for reasons that are not well understood. There may be an as yet undefined genetic susceptibility to develop PAH amongst patients with CHD, which persists even after haemodynamic intervention in early childhood. Furthermore, patients with anatomically complex CHD, who are now surviving into adulthood following improvements in palliative procedures and patients from developing countries, who have not received an early diagnosis (and repair) of CHD contribute to the pool of patients who go on to develop PAH. Irrespective of pathogenetic mechanism(s), current evidence suggests that the presence of PAH in the CHD setting has an adverse impact on both quality of life and survival [3]. Eisenmenger syndrome (ES) represents the extreme end of the PAH–CHD spectrum and displays a prevalence of 1.1% to 12.3% amongst CHD patients [2,3], and a prevalence of 0.001% in the general population [5]. The exact number of patients with ES worldwide remains unknown [6]. We have observed a trend of an approximate 9% year-on-year increase in the number of patients with ES attending our designated tertiary CHD–PAH service over the past 8 years (personal communication, Professor Gatzoulis, Royal Brompton Hospital, London, UK). We submit this reflects improving awareness of the condition in the community and availability of therapy, rather than increasing numbers of patients with ES in the UK. Nevertheless, the anticipated growth in numbers and complexity of adult patients with CHD [7], including those with PAH, means the

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need for information on how to care for these patients will become increasingly relevant and pressing for cardiologists and other healthcare professionals alike. Clinical and academic interest in PAH–CHD as a disease entity has grown in recent years [8]. Considerable progress has been made; but there remain multiple challenges concerning optimal classification, monitoring and therapy. A meeting was held in Vienna (February 2011) in which 63 PAH–CHD experts from around the world gathered to discuss the most salient of these issues. In this article, we, the Scientific Committee of the meeting, report on some of the meeting's debates and supplement this with our personal experiences and the very latest literature in this rapidly expanding field of cardiovascular medicine. 2 . Search strategy and selection criteria We searched MEDLINE (01/01/2003–31/12/2013) using the search terms ‘congenital heart disease’ in conjunction with ‘pulmonary arterial hypertension’ or ‘Eisenmenger syndrome’ or ‘Fontan circulation’. We selected publications from the past 5 years, but did not exclude older, commonly referenced and highly regarded publications. We also included well-known, relevant publications that we considered important, such as clinical guidelines that were not identified using the search strategy. 3. Classification of patients with pulmonary arterial hypertension in association with congenital heart disease A wide range of defects are often associated with PAH and patients with PAH–CHD represent a heterogeneous group. While it is necessary for CHD specialists to possess and apply a detailed descriptive classification system of PAH–CHD (please refer to Table 7 in the joint European Society of Cardiology/European Respiratory Society [ESC/ERS] guidelines for the diagnosis and treatment of pulmonary hypertension) [1] this can be overly complex and unworkable for the non-CHD expert. A simple, practical system of identifying PAH–CHD patients is clearly needed, so that cardiologists, pulmonologists and other healthcare professionals can readily recognise patients who have been lost to followup and refer them to specialist tertiary care. An example of a simplified classification system has been proposed by an expert consensus panel and categorises patients with PAH–CHD into four groups (please refer to Table 6 in the ESC/ERS guidelines) [1]. We have developed this system further and provide a modification of this table and a graphical representation of the four PAH–CHD patient groups (see Fig. 1) [1]. Furthermore, we also discuss the Fontan cohort, patients who do not fulfil the criteria for diagnosis of PAH, but nevertheless merit consideration. 3.1. Eisenmenger syndrome (Fig. 1A) and chronic cyanosis 3.1.1. Historical context In 1897 Viktor Eisenmenger first described a typical example of the syndrome that would later bear his name with a detailed anatomical and clinical account of a man with cyanosis and a ventricular septal defect (VSD). It took more than 50 years for clinicians to recognise that the cyanosis present in this setting resulted from a bidirectional or reversed shunt caused by pulmonary hypertension. Accordingly, ‘Eisenmenger complex’ was defined as PAH with bidirectional or reversed shunt through a large VSD. Working in London in the 1950s, it was Paul Wood who realised that the position of the shunt, i.e. the type of defect, was of little relevance when it came to the clinical phenotype and physiology of a large and non-restrictive communication between the pulmonary and systemic circulation. Given the number of different anatomical cardiac defects that can lead to the same clinical course of progressive PAH–CHD with an eventual reversal of the shunt from left to right to right to left and the development of chronic cyanosis, he proposed that the term ‘Eisenmenger syndrome’ be extended to

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characterise this clinical entity, irrespective of the anatomy of the underlying cardiac defect [11,12]. Although the all-encompassing definition of ES bequeathed by Dr Wood is still in use today, there is some controversy as to whether simple atrial septal defects (ASDs) should be included in the ES group. It is true that the majority of patients with an ASD do not develop PAH early in life but it is also true that the prevalence of ASD is higher amongst patients with PAH than those without. Furthermore, there appears to be a cause and effect relationship between large left-to-right shunts and progression to ES over time, although this clinical course does not apply to all patients. We speculate that a permissive genotype, which remains to be determined, ‘allows’ a minority of patients with a large ASD to develop ‘aggressive’ PAH that eventually leads to ES. Furthermore, there is evidence that this group of ES patients with an ASD do respond to oral PAH-specific therapy in a similar manner to those with ES and a VSD [13]. 3.1.2. Management and treatment options Patients with ES display chronic cyanosis and, typically, multi-organ, multi-system involvement [14,15]. Chronic cyanosis has a detrimental effect on exercise capacity [16] but it is also a powerful stimulus for secondary erythrocytosis which, in turn, increases oxygen carrying capacity and, therefore, enhances tissue oxygenation and prevents, at least in part, hypoxic end-organ damage [14]. This desirable and naturally occurring adaptive mechanism of secondary erythrocytosis is often mislabelled as polycythaemia. This error is not simply an issue of semantics: polycythaemia affects all three haematopoietic cell lineages and is linked historically with complications such as hyperviscosity syndrome, pulmonary embolism and stroke [16]. Hyperviscosity syndrome in ES patients is relatively rare and presents with non-specific symptoms (headache, muscle weakness, fatigue etc.) that mimic those of iron deficiency, a common occurrence in ES. The long-standing and inappropriate practice of periodic venesection to counteract secondary erythrocytosis and ostensibly to convey shorter- or longer-term symptomatic relief in ES patients [17], lacks both rationale and evidence. Despite good intentions, venesections compromise oxygen tissue delivery, reduce exercise capacity and increase rather than decrease the risk of stroke [18]. Our practice has changed a great deal in this matter: routine venesections have been abandoned, iron deficiency is routinely investigated [19] (as it is common even in venesection-naïve patients [18]) and iron deficient patients routinely receive iron supplements. A recent pilot/ intention-to-treat study [20] demonstrated an increase in haemoglobin levels following 3 months of iron supplementation, which was matched by improvements in 6-minute walk distance (6MWD) and quality of life scores based on the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) disease-specific questionnaire. The diagnosis of iron deficiency in ES should not be based on haemoglobin or mean cellular volume levels. We employ ferritin b 20 mg/L or ferritin b 50 mg/L and transferrin saturation of b20% as the main diagnostic markers for iron deficiency in this population; levels of expression of the transferrin receptor can also be used. There is, nevertheless, a need for further refining the diagnostic criteria for iron deficiency in this setting and for a greater understanding of the adaptive mechanisms between chronic cyanosis, secondary erythrocytosis, iron metabolism/utilisation and endothelial dysfunction [21], all of which may shed more light on pathogenesis and further improve therapy for this group of patients. There is growing evidence for the prognostic significance of exercise in CHD in general [22,23], and especially in ES patients [24,25]. Furthermore, there was a recent report on the safety and benefits of exercise training in patients with PAH–CHD [26], reinforcing the potential benefits of exercise in this specific patient cohort [27]. Therefore, guided patient-specific exercise training and physical activity [28], as well as avoidance of smoking and obesity and the exclusion of associated sleep apnoea, should be considered and discussed with the patient at the clinic.

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A

C

B

D

Fig. 1. Clinical classification of pulmonary arterial hypertension in association with congenital heart disease. (A) Eisenmenger syndrome: Patients with left-to-right shunts due to large defects (atrial, ventricular [as depicted here] or arterial, e.g. patent ductus arteriosus) leading to severe PAH and, with time, to reversal of shunting. Chronic cyanosis with secondary erythrocytosis and multi-organ involvement are typically present in these patients. There is currently evidence to support PAH-specific therapy for functional class III patients in this group. (B) PAH associated with left-to-right shunts: Patients with sizeable defects and mild-to-moderate PAH who shunt predominantly left to right and are not cyanosed at rest (i.e. patients who have not developed reversal of shunting). These patients have the potential to develop Eisenmenger syndrome over time. Surgical or catheter interventions addressing the haemodynamic lesion in this setting are controversial and unlikely to convey long-term benefits if patients have elevated pulmonary vascular resistance (as haemodynamic intervention(s) do not seem to reverse established pulmonary vascular disease). The decision to intervene should not be based on the feasibility of the procedure. A proposed ‘treat and repair approach’ lacks support from any prognostic data [9] and should be discouraged. In contrast, treatment with PAH-specific therapy may have a role in this patient group [10] , although controlled data are lacking at present. (C) PAH with small or coincidental defects: Patients with relatively small defects who have developed PAH that cannot be solely attributed to CHD. These patients should be treated with PAH-specific therapy and their small heart defects should not be closed. (D) PAH after surgical or percutaneous correction: Patients who present with progressive PAH early or late after repair of CHD in the absence of large residual haemodynamic lesions from the original operation. Such patients seem to have survival rates similar to patients with idiopathic PAH and worse than patients with PAH and open defects and even patients with ES [10]. Consequently, these patients with PAH after reparative cardiac surgery for CHD should be treated with PAH-specific therapy.

There are a number of ‘conventional therapies’ used to treat PAH, such as supplemental oxygen and calcium channel blockers. However, the evidence base for these as symptomatic therapies in ES patients is sparse. Although a small study demonstrated an acute rise in oxygen

saturation following 40% oxygen supplementation [29], a 2-year controlled study of nocturnal oxygen supplementation in adults with ES failed to show survival benefits [30]. While some patients may claim symptomatic benefits from nocturnal oxygen administration, there is

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no evidence at present to support continuous oxygen use, especially given its potentially adverse impact on physical activity. Similarly, the efficacy of calcium channel blockers in patients with ES is unproven and their use is not recommended because of their potential to increase right-to-left shunting, which can lead to profound cyanosis, syncope and sudden cardiac death [31,32]. Anticoagulation may be considered, although a consensus for its routine use in ES patients is lacking at present. There may be other indications for anticoagulation in adult ES patients, such as clinical arrhythmia and/or ventricular dysfunction. It would seem prudent to involve haematological expertise in titrating therapy when anticoagulation is commenced given the known bleeding versus thrombotic diathesis in these patients. There is recent and growing evidence showing the safety and efficacy of PAH-specific therapies in ES patients. There are three established classes of PAH-specific medication: endothelin receptor antagonists, phosphodiesterase-5 inhibitors and prostacyclins [33–35], as well as a novel class termed soluble guanylate cyclase stimulators [36]. The endothelin receptor antagonists which include bosentan, ambrisentan and macitentan, work by blocking the deleterious effects of elevated levels of endothelin-1, a potent vasoconstrictor and mediator of proliferation, fibrosis and inflammation, which are known factors in the pathogenesis of PAH. Sildenafil and tadalafil are vasodilators that belong to the phosphodiesterase-5 inhibitors drug class and work in PAH by targeting the nitric oxide pathway through prevention of the breakdown of cyclic GMP in the endothelium of the pulmonary vasculature. This in turn decreases the availability of calcium for vascular smooth muscle cell contraction. Prostacyclin and its analogues, such as treprostinil and iloprost, activate prostanoid receptors expressed on endothelial cells within the pulmonary vasculature resulting in vasodilation. Riociguat, a soluble guanylate cyclase stimulator, also works on the nitric oxide pathway and enhances the production of cyclic GMP.

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Given the history of inappropriate medical interference in the treatment of ES patients and the complex adaptive mechanisms involved, it was paramount that safety was addressed before efficacy in this patient group when new oral PAH-specific therapies became available. This point was addressed in the Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5), which included safety as a primary endpoint [37]. Data from BREATHE-5 showed no adverse effect on oxygen saturation after 16 weeks of bosentan therapy compared with placebo, and treatment was well tolerated. Patients on bosentan treatment had improved pulmonary vascular resistance index (Fig. 2A) and 6MWD (Fig. 2B) compared with controls [37]. Furthermore, treatment effect of bosentan was observed in patients with ASD and VSD to a similar extent [13]. The increase in pulmonary vascular resistance index demonstrated in the placebo (natural history) arm of this study highlights the progressive nature of this condition. The data obtained from BREATHE-5 demonstrated that haemodynamic and functional benefits could be achieved in ES patients, who were previously thought to have a fixed pulmonary vascular resistance. The increase in 6MWD was maintained in patients subsequently treated with bosentan for 24 weeks in the open-label extension study [38]. However, in studies of up to 2 years duration, initial improvements in 6MWD observed during the first few months of treating PAH–CHD patients with bosentan were not maintained over the long term [39,40]. While there is evidence showing that bosentan improves exercise capacity in the short term, further studies are required to fully understand its long-term benefits. There are no randomised data describing the use of ambrisentan in ES patients as patients with PAH–CHD were not included in the pivotal registration trials [43]. However, preliminary data from 17 ES patients treated with ambrisentan at a single centre indicate that it may improve exercise capacity in the short term and stabilise functional class over the

A

B

C

D

Fig. 2. (A) BREATHE-5 [37]: Percentage change in pulmonary vascular resistance index from baseline following placebo or bosentan treatment for 16 weeks. Note the fall in pulmonary vascular resistance index in the active bosentan arm which challenges the concept of fixed pulmonary vascular disease. Also note the increase in pulmonary vascular resistance index in the placebo arm within the 16-week study period, suggestive of the progressive nature of ES although the changes were small. (B) BREATHE-5 [37]: Change in 6MWD from baseline following placebo or bosentan treatment for 16 weeks. Note this change has a significant impact on functional capacity and quality of life given the major physical limitations of patients with ES. (C) Tay et al. [41]: Improvement in CAMPHOR, a quality of life measure specific for pulmonary hypertension, from baseline following 12 weeks of sildenafil therapy. (D) Dimopoulos et al. [42]: Survival benefit in ES patients treated with PAH-specific therapies versus untreated patients or patients receiving ‘conventional’ therapy. Note these data refer to a contemporary rather than a historic control group. Propensity score analysis was applied (for full details see text).

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longer term [44]. Macitentan was approved for the treatment of PAH in October 2013. The 62 PAH–CHD patients included in the pivotal trial represented less than 10% of the total patient population [45]. Clinical trials specific to patients with PAH–CHD are required to examine the efficacy and safety of both these endothelin receptor antagonists in this specific PAH population. Regarding phosphodiesterase-5 inhibitors, there are two controlled studies of tadalafil [46,47] that demonstrate increasing 6MWD and decreasing pulmonary vascular resistance with improving oxygen saturation compared with placebo after 6 weeks [46] and 12 weeks [47] of therapy. There are data from intention-to-treat studies with sildenafil that show safety and improved 6MWD, functional capacity and quality of life (Fig. 2C) [41]. A longer term study involving 84 ES patients treated with sildenafil for 12 months has confirmed significant improvements in exercise capacity (56 m increase in 6MWD from baselinep b 0.0001) and improvements in haemodynamics (mean pulmonary arterial pressure and pulmonary vascular resistance index) albeit in an open-label fashion [48]. There are also data on the potential role of prostacyclins in the ES population from non-controlled studies. Beneficial effects on haemodynamics, functional class and exercise capacity have all been reported in small cohort studies with intravenous, subcutaneous or nebulised administration of prostacyclins [49–52]. However, given the challenges of administration and the risks of line sepsis and systemic embolism (high in this patients group with right-to-left shunting) compared with the alternative of oral therapy, prostacyclins do not represent the first-line treatment choice. Nevertheless, one can anticipate their potential contribution in combination with oral therapies. Finally, the registration trial of riociguat [53], approved for treatment of PAH in October 2013, included 35 PAH–CHD patients (10% of the total population). Clearly, more evidence on the risk–benefit profile for this patient population is required before recommendations on the use of riociguat can be made. Patients with Down's syndrome [54,55], who constitute a significant proportion of the patients in current ES cohorts and patients with segmental PAH (i.e. PAH in one lung or part[s] of a lung) [56] seem to have a similar and positive clinical response to oral PAH-specific therapy, although this is based on non-controlled data. Combination therapy, recommended in the ESC/ERS guidelines [1], when treatment goals are not met, is now increasingly employed for ES. There have been two main studies examining the combination of bosentan and sildenafil in ES patients [57,58]. ES patients on a stable dose of bosentan for 9 months were randomised to placebo or sildenafil for 3 months with a further cross-over period of 3 months; 6MWD improved with bosentan therapy, with no further improvement when sildenafil was added. Oxygen saturation at rest, however, improved with the addition of sildenafil [57]. Administration of sildenafil improved 6MWD, oxygen saturation and haemodynamics in the second study of patients with ES or PAH–CHD experiencing clinical decline while on bosentan therapy [58]. Combination therapy appeared to be well tolerated in both studies. While improving the patient's functional capacity and quality of life are primary treatment goals, prolonging life is equally important as a therapeutic target. A recent, single-centre, retrospective report describing a contemporary cohort of 229 adult ES patients provided evidence of survival benefits with the use of PAH-specific therapy [42] . Sixty-eight of the 229 patients participating in the study received PAH-specific therapy (75% of them on bosentan and all but one of the remainder on sildenafil). Initiation of PAH-specific therapy was based either on enrolment into study protocols, or on clinical grounds (i.e. those in functional class III since 2006, when safety and efficacy data from BREATHE-5 became available) and following discussion of potential symptomatic benefits with patients. Fifty-two of the 229 patients died during a median follow-up of 4 years; only two of them were receiving PAH-specific therapy at the time of death. This study represents the first evidence of survival benefits in ES patients on

PAH-specific therapy (Fig. 2D) in a contemporary and non-historic comparison, albeit retrospective in nature. In parallel to these recent therapeutic advances, progress is also being made on improving monitoring and refining prognostication for patients with ES. Given the natural history/clinical phenotype of this condition and its distinct differences when compared with other PAH aetiologies (including chronic cyanosis) [59], a modification of the widely used ESC/ERS guidelines table on severity, stability and prognostic parameters in PAH [1], provided herewith, is necessary. Our ESspecific table (Table 1) takes into account the intricacies of this patient population, together with the latest available data on disease monitoring, disease progression and prognostication. This table, we submit, will facilitate an improved and standardised approach to monitoring ES patients, by grading disease severity and disease progression and enabling timely initiation or uptitration of therapy and assessment of the response to it. Furthermore, other aspects of care need to be discussed with and applied to the individual patient: physical conditioning [26]; avoidance of risk factors, such as smoking and obesity; and the identification and treatment of sleep apnoea are all important. 4. Other PAH associated with CHD (non-Eisenmenger syndrome): Fig. 1B–D In addition to patients with ES, there are four other groups of CHD patients who have lifestyle limitations placed on them as a result of their pulmonary vascular involvement. 4.1. PAH associated with left-to-right shunts: Fig. 1B Treatment of patients with PAH and moderate-to-large defects who are still shunting left to right at rest, whether by haemodynamic intervention or PAH-specific therapy, is controversial at present. Haemodynamic interventions in CHD are predominantly aimed at reducing symptoms and improving long-term prognosis. In general, pulmonary vascular disease is not reversed if left-to-right shunting is abolished by intervention in adulthood. For example, most patients with large VSDs go on to develop pulmonary vascular disease within their first 1–2 years of life, hence the urgency to establish this diagnosis and intervene early. Some paediatric cardiologists may choose to close such a defect beyond early childhood on the assumption that this may improve prognosis. Such an approach, however, is questionable. Recent data from a case series of 38 patients showed that one-fifth of patients had a poor sort-term outcome following surgical closure of the VSD in the presence of elevated pulmonary vascular resistance [64]. Five patients died immediately after surgery, one died 6 months later and two were reported to have persistent severe PAH. Longer term data from this cohort are lacking, but there is legitimate concern that patients with established pulmonary vascular disease may have a prognosis that is unlikely to be influenced through surgical intervention. With the advent of PAH-specific therapy and the possibility of decreasing pulmonary vascular resistance over the long term, the question has been raised as to whether such medications could be used to pharmacologically ‘prepare’ PAH–CHD patients for surgical or catheter interventions [6] — i.e. the ‘treat and repair approach’ [65]. There may be a rationale for treating patients with raised pulmonary vascular resistance and persistent left-to-right shunting with PAH-specific therapy [10], which could then be followed by a reassessment for operability, but data are limited at present [9]. Theoretically, patients who demonstrate a dramatic response to therapy could be operated on in an attempt to avoid further progression of the disease by abolishing the shunt. While there are case reports of good short-to-mid-term outcomes for this strategy [66–69], the long-term impact of such an approach remains unknown. This uncertainty is reflected in the latest consensus from the 2013 World Congress on Pulmonary Hypertension in Nice, which recommended that even patients with mild elevation of pulmonary vascular resistance (2.3–4.6 Wood units) should be

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Table 1 Monitoring and prognostication the adult Eisenmenger syndrome patient. Better prognosis

Determinants of prognosis

Worse prognosis

No No I, II Longer (N350 m) N85% Transferrin saturation ≥20% Normal or near normal TAPSE ≥ 1.5 cm RA area b 25 cm2 RA/LA b 1.5 RAP b 8 mm Hg and CI ≥ 2.5 L/min/m2

Right ventricular failurea Syncopeb WHO functional classc [42] 6MWD [24,25] Oxygen saturation [24,25] Iron deficiency [60] BNP plasma levelsd Echocardiographic findingse

Yes, guarded Uncertain III, IV Shorter (b300 m) b85% or a drop of N2%/year Transferrin saturation b 20% N30 pmol/L TAPSE b 1.5 cm RA area ≥ 25 cm2 RA/LA ≥ 1.5 RAP N 15 mm Hg and CI ≤ 2.0 L/min/m2

Haemodynamicsf

BNP, brain natriuretic peptide; CI, cardiac index; LA, left atrium; RA, right atrium; RAP, right atrial pressure; 6MWD, 6-minute walk distance; TAPSE, tricuspid annular plane systolic excursion; WHO, World Health Organization. a Presence or absence of right ventricular failure in PAH is deemed to carry a worse or better prognosis respectively. However, in patients with ES right ventricular failure is a late and ominous sign and thus of limited value for early prognostication. b Syncope in patients with ES and chronic cyanosis can be vasovagal, due to autonomic nervous dysfunction; therefore, if syncope is present, its prognostic value is assumed to be uncertain. c Overall 5-year mortality amongst aduts with ES was higher in functional class III patients compared with patients in functional class I or II (14.1% versus 32.2%; log rank p = 0.006) [42] d A plasma BNP value of N30 pmol/L has been shown to convey a 4.5-fold greater mortality risk in ES patients (normal values b 20 pmol/L) [61]. e Echocardiographic parameters specific for ES patients; a composite score, including tricuspid annular plane systolic excursion b 1.5 cm, ratio of right ventricular effective systolic to diastolic duration ≥ 1.5, right atrial area ≥ 25 cm2 and a ratio of right atrial to left atrial area ≥ 1.5 was highly predictive of clinical outcome (area under the curve 0.90 ± 0.01) [62]. f Baseline haemodynamic assessment, including measurement of pulmonary vascular resistance, is the norm in most tertiary centres. Repeated, serial haemodynamic assessments are not, however, routinely recommended for patients with ES. Acute vasoreactivity studies during baseline haemodynamic assessment may convey prognostic information [63].

evaluated in tertiary centres, where the pros and cons of a potential defect closure can be properly considered and discussed with the individual patient [70].

with PAH after reparative surgery for CHD should be treated with PAHspecific therapy as dictated by the severity and course of their disease. 5. Patients with a Fontan circulation

4.2. PAH with a small or coincidental defect: Fig. 1C Patients with PAH and a relatively small defect (coincidental defect), which in itself is not thought to be responsible for the development of PAH, are not uncommon. Clearly, there is no indication for cardiac surgery or catheter defect closure in this patient group. Indeed, the presence of the defect may convey an advantage to the patient by allowing for right-to-left shunting and maintenance of the systemic cardiac output, albeit at the expense of cyanosis. No such ‘relief valve’ exists in idiopathic PAH, where selected patients may be occasionally considered for atrial septostomy. Patients with PAH and small, coincidental defects should be treated with PAH-specific therapy. 4.3. PAH after surgical or percutaneous correction: Fig. 1D This is a relatively small group of patients who present with PAH years after previous repair of CHD. These patients may have developed PAH because of late diagnosis and intervention, or perhaps they were genetically or developmentally predisposed to develop PAH and this predisposition was not altered by childhood surgery or catheter intervention. This group of patients remains a concern, because of the lack of a) detailed preoperative data and information on how the decision was made to proceed and b) complete, serial, long-term follow-up information as more than 50% of CHD patients are lost to life-long cardiac follow-up [4] and thus the denominator remains uncertain. Given recent descriptive data suggesting that 5–10% of hospital cohorts of adult patients with CHD have PAH [2,3,71], we suggest that every patient with CHD merits at least one thorough assessment in a specialist centre during teenage or adulthood years (to confirm the presence or absence of PAH) [72]. Additional information on prognosis, health care needs [73], life planning [74,75], including advice on vocational choice, reproduction and contraception (pregnancy remains a high-risk endeavour in patients with PAH) [75] should also be provided during such an assessment. Late presentation of PAH after intervention for CHD further calls into question the appropriateness of late surgical and catheter intervention for CHD, where decisions can be incorrectly based on procedural feasibility and peri-procedural risks, rather than the potentially adverse long-term impact of such interventions. Patients

We decided to include patients with a Fontan circulation in our discussion although, strictly speaking, they do not meet criteria for PAH; this is because of recent evidence of an abnormal vascular bed in the Fontan setting of low cardiac output and apparently increased pulmonary vascular resistance [76–81], which may be modulated by PAHspecific therapy [82–84]. The Fontan physiology illustrates well why assessment of pulmonary vascular resistance in CHD is paramount; mean pulmonary arterial pressure in Fontan patients is lower than 25 mm Hg and yet pulmonary vascular resistance may be high, particularly in adult patients. There is a rationale, therefore, for examining the potential safety and efficacy of PAH-specific therapy in the increasing number of Fontan patients, including those with a ‘failing Fontan circulation’, who have a poor prognosis and extremely limited surgical or other therapeutic options. Objective exercise capacity may serve as a primary endpoint and, ideally, patients should be recruited to studies before clinical decompensation and multi-organ failure ensue. Such data are however, limited at present. We submit that additional investment is due, with randomised controlled studies required in this population who lack a subpulmonary ventricle, before recommendations for PAH-specific therapy can be made. 6. Summary There is clear evidence that PAH-specific therapy is well tolerated and conveys symptomatic and survival benefits in patients with ES. Many of these patients are lost to follow-up and should be brought back into tertiary care and offered PAH-specific therapy, when in functional class III. Given the progressive nature of ES, there is also a rationale for treating patients who have been diagnosed early, i.e. in functional class II (in contrast with idiopathic PAH where delays in establishing a diagnosis are common). However, even ES patients may be lost to follow-up and can present to tertiary centres late in the course of their disease. Further studies in this area are clearly needed to establish the role of early treatment in ES. With regards to PAH and left-toright shunts, patients should only undergo defect repair, if a clear and long-standing benefit from such intervention can be demonstrated. The exact circumstances in which this can be sufficiently guaranteed

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are currently uncertain, and either surgical or catheter therapy may have long-term detrimental effects in these patients. There are ongoing discussions on the potential role of ‘a treat and repair approach’ in this setting, but no substantive evidence to support it. Furthermore, decisions to proceed with repair based on procedural feasibility and peri-operative survival prospects may compromise the long-term prospects for such patients by converting the disease to a more aggressive and malignant form of PAH. Patients with PAH and left-to-right shunts clearly need to be assessed in tertiary centres. Patients with small, coincidental defects and patients with PAH after CHD repair should be treated with PAH-specific therapy because their disease course can be more aggressive than ES, and bears similarities to idiopathic PAH. Finally, there are patients with CHD and milder forms of PAH or patients with raised pulmonary vascular resistance but no PAH per se, such as patients with a Fontan circulation who may also benefit from pharmacological intervention with PAH-specific therapies. Data and further investment in these CHD subgroups are clearly required. Looking ahead, national and international registries should provide a better understanding of the epidemiology, genetics, natural history, and therapeutic outcomes of this heterogeneous PAH patient population. We suggest that randomised controlled trials assessing the benefits of PAH-specific therapy should now be extended to ES patients in functional class II, to those with pre-ES and to those with a Fontan circulation. Other management recommendations, such as abandoning venesections, providing iron supplementation and adopting a standardised assessment approach for ES, as presented herewith, should be applied widely and validated prospectively, so that more patients with PAH associated with CHD benefit in the future.

Conflicts of interest statement MAG has served on the advisory boards of Actelion Pharmaceuticals UK and Actelion Pharmaceuticals Ltd, Pfizer UK, and GlaxoSmithKline and has received unrestricted educational grants from Actelion Pharmaceuticals Ltd and Pfizer UK. MB has served as a consultant or advisory board member for Actelion Pharmaceuticals Ltd, Bayer, Eli Lilly, GlaxoSmithKline, Novartis, and Pfizer, has received grants from Actelion Pharmaceuticals and Bayer, lecture fees from Actelion Pharmaceuticals Ltd, Bayer, and Pfizer and has developed educational materials for Actelion Pharmaceuticals Ltd and Pfizer. MJL has served as a consultant, advisory board or research Steering Committee member for Actelion Pharmaceuticals Ltd. He has also participated in trial conception and completion with support from Pfizer, Actelion Pharmaceuticals Ltd, Myogen, and NITROX and has received trial grant support from Actelion Pharmaceuticals Ltd and Myogen. NG has participated in advisory board activities for Actelion Pharmaceuticals Ltd, Pfizer, United Therapeutics, Eli Lilly, Bayer-Schering, Encysive, and GlaxoSmithKline, given paid lectures for Actelion Pharmaceuticals Ltd, Pfizer, Bayer-Schering, and Encysive, and his institution has received research grants from Actelion Pharmaceuticals Ltd, Pfizer, United Therapeutics, Eli Lilly, BayerSchering, Encysive, and GlaxoSmithKline.

Contributions The idea of the paper was conceived by us, the Steering Committee, during a meeting of 63 international cardiac experts held in Vienna in 2011. This paper reports some of the meeting's discussions, supplemented with our personal experience and the very latest literature. Michael Gatzoulis wrote the paper and selected the references from the literature search to be included. Maurice Beghetti, Michael J Landzberg and Nazzareno Galiè critically reviewed and revised the paper and suggested additional, supplementary references. All authors have approved the final version of the manuscript.

Acknowledgement We thank Lisa Thomas (Elements Communications Ltd, Westerham, UK) for her assistance with copyediting and illustrations, supported by Actelion Pharmaceuticals Ltd and Dr Kostas Dimopoulos for his helpful critique on the manuscript.

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