Eisenmenger syndrome and other types of pulmonary arterial hypertension related to adult congenital heart disease

Abstract

Introduction: Eisenmenger syndrome (ES) is the most advanced form of pulmonary arterial hypertension (PAH) in patients with congenital heart disease (CHD). It is characterised by a severe rise in pulmonary vascular resistance resulting in shunt reversal and cyanosis.

Areas covered: In this paper, an overview of ES and other types of PAH related to CHD (PAH-CHD) in adults is provided. The modern management of PAH-CHD in tertiary centers, with emphasis on co-morbidities and complications is described.

Expert opinion/commentary: PAH-CHD is a wide spectrum of conditions, of which ES is the archetype. The size and location of the shunt, the degree of adaptation of the right ventricle to the increased afterload and other compensatory mechanisms, such as secondary erythrocytosis, define the clinical presentation and natural history of these patients. PAH therapies have improved the quality of life and outcome of many patients with PAH-CHD, but expert multidisciplinary management remains essential in optimising the care of this rare and complex group of patients.

Keywords: pulmonary arterial hypertension, congenital heart disease, Eisenmenger syndrome, cyanosis, secondary erythrocytosis

Abstract count (text): 173

Article highlights 

· Eisenmenger syndrome is characterised by the triad of a significant cardiac defect, severe pulmonary hypertension and long-standing cyanosis, with consequent multiple organ involvement.

· Right heart catheterisation, with careful calculation of pulmonary vascular resistance, is required for a formal diagnosis of pulmonary arterial hypertension. In many adult patients with large post-tricuspid shunts and cyanosis, however, visualisation of a low-velocity, bi-directional shunt on imaging is highly suggestive of Eisenmenger physiology. Experts may choose to forego catheterisation in such cases.

· Defect repair should not be attempted in Eisenmenger syndrome or other pulmonary arterial hypertension related to congenital heart disease with significant pulmonary vascular disease, although there is a large “grey area” in the guidelines and expertise should be sought on an individual-case basis.

· Pulmonary arterial hypertension therapies can be helpful in Eisenmenger patients to improve haemodynamics, exercise capacity and quality of life, along with standardised, supportive care and avoidance of harmful practices e.g. venesection.

· Regular follow-up in specialist centres and a multi-disciplinary approach is required when managing patients with Eisenmenger syndrome, combining expertise from pulmonary hypertension, congenital heart disease and other disciplines.

Introduction

Eisenmenger syndrome (ES) is the most severe form of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD). [1] In ES and other types of PAH related to CHD (PAH-CHD), pulmonary vascular disease (PVD) is the result of uncorrected congenital cardiac defects allowing significant systemic-to-pulmonary shunting, with pressure and/or volume loading and shear stress to the pulmonary circulation. In most cases of ES, a large post-tricuspid defect, such as a ventricular septal defect (VSD), patent ductus arteriosus (PDA) or aortopulmonary window, allows significant systemic-to-pulmonary shunting with equalization of pressure between right and left ventricles and the pulmonary artery during childhood. This, in turn, leads to pulmonary arteriolar histologic changes and a progressive decrease of the overall cross-sectional area with concomitant rise in pulmonary vascular resistance (PVR) and reduction in systemic-to-pulmonary shunting. When PVR reaches systemic levels, bidirectional shunting occurs leading to desaturation of systemic arterial blood. In other forms of PAH-CHD, the PVD may not be severe enough to reverse the shunt (PAH-CHD with systemic-to-pulmonary shunting), or it may occur or persist after repair of the defect. Finally, there is a minority of patients with a small cardiac defect and significant PAH, who have a similar phenotype to idiopathic PAH.

ES is a complex and multisystem disorder, with a high mortality and significant morbidity [2]. PAH also significantly affects outcome in patients with other types of PAH-CHD.

In this paper, ES and other types of PAH-CHD are described in terms of pathophysiology, clinical presentation and state-of-the-art management in an expert PAH-CHD tertiary center.

Anatomy, pathophysiology and clinical presentation

The first description of ES was of a man with a large VSD published in 1897 [3]. Over half a century later, Paul Wood published a series of lectures delivered before the Royal College of Physicians of London. His systematic description of a series of ES cases included a wide variety of CHD, with severe PAH “due to a high pulmonary vascular resistance with reversed or bidirectional shunt” at atrial, ventricular or great artery level [4]. The risk of developing PAH and ES depends on the location and size of the shunt lesion, as well as concomitant factors, such as the presence of Down syndrome.

Shunting associated with PAH may occur at different levels. The underlying congenital heart defects can be divided into pre-tricuspid, as in the case of an atrial septal defect (ASD), and post-tricuspid, i.e. VSD, PDA, aortopulmonary window and various forms of truncus arteriosus. Surgical systemic-to-pulmonary palliative shunts, such as the Waterston and Potts shunt, aimed at augmenting pulmonary blood flow have often been associated with the development of PAH [2,5,6]. PAH in post-tricuspid shunts typically develops during childhood and is severe when the defect is large [6,7]. The rate of progression of PVD varies between individuals, with some patients developing severe PAH reversal of the shunt early in life (especially patients with Down syndrome), while in others, the disease progresses more slowly, and severe PVD may only occur in the second or third decades of life. The timing of the development of PVD depends on the type of defect. For example, patients with transposition of the great arteries and a ventricular septal defect develop pulmonary vascular disease sooner than patients with an isolated ventricular septal defect, whilst patients with large ASD who develop PAH, do so much later. In patients with aortopulmonary window and truncus arteriosus, there is also an early and rapidly progressive rise in PVR [8,9].

Pre-tricuspid shunts may also be infrequently associated with PAH, typically later in life, even though the mechanisms behind this remain unclear. ASDs can cause volume but no significant pressure load to the pulmonary circulation. Pulmonary pressure can increase in the presence of large shunts, but without a rise in PVR, hence without PVD. In a minority of patients, in whom there may be a genetic predisposition, PVR can rise even to systemic levels with reversal of the shunt, described as “Eisenmenger ASD”. Of course, the direction of shunting through an ASD is not just dictated by PVR, but also by the relative compliance of the two ventricles. Hence, a decrease in right ventricular compliance in a hypertensive, hypertrophied RV is also responsible for the reversal of the shunt through an ASD [10,11].

There is a high likelihood that genetic factors play an important role in PAH-CHD, although few major genetic abnormalities have been identified to date. Zhu et al. recently reported on the results of an international genetic cohort of patients with PAH-CHD, compared to idiopathic and familial PAH. They estimated that rare deleterious variants contribute to approximately 3.2% of PAH-CHD cases. SOX17, a novel candidate risk gene, is highly constrained and encodes a transcription factor involved in Wnt/β-catenin and Notch signaling during development. A genetic substrate may help to explain the significant heterogeneity in the timing and mode of presentation of PAH in patients with similar underlying CHD. It may also explain why a minority of patients with pre-tricuspid shunts unexpectedly develop PAH [12].

The structural changes in the pulmonary vascular bed are dynamic and multifactorial, and include endothelial dysfunction, vasoconstriction and remodeling of the pulmonary arteries. The histopathologic classification proposed by Heath and Edwards still applies and is used in a modified form when performing lung biopsies for assessing operability (Table 2). Biopsies are, however, very rarely performed nowadays and the decision to operate is usually based on the clinical presentation, imaging findings and invasive hemodynamic parameters [1,5].

Other groups of CHD patients liable to developing PH include those with left heart disease (group 2 in the international PH classification), congenital lung abnormalities (group 3), peripheral pulmonary stenosis (group 4), Fontan-type circulations and segmental PH (typically patients with pulmonary atresia or complex anatomy with branch pulmonary stenosis (group 5) [2,13,14]. The focus of this review is PAH-CHD (group 1), and especially ES (subgroup A of the PAH-CHD classification, Table 1)[2].

The clinical manifestations of PAH-CHD vary significantly according to the type and severity of the underlying cardiac lesion, patient age and prior repair or palliation. Common manifestations of PAH of any aetiology include marked exercise intolerance, with dyspnea and fatigue. It is important to remember that PAH-CHD patients may have a different perception of their symptoms compared to those with other types of PAH, through adaptation to a long-standing condition, which has often been present since childhood. Indeed, ES adult patients often report minor exercise limitation, even when found to be severely limited by objective assessment (e.g. cardiopulmonary exercise testing). When carefully questioned about their activities, they typically report avoiding strenuous efforts and tend to perform activities a slower pace than their peers. For this reason, assessment of WHO functional class can be misleading in PAH-CHD [5,15,16].

Other common symptoms include peripheral or abdominal swelling, syncope, worsening cyanosis (usually reported by relatives or partners), palpitations and hemoptysis. These and other symptoms may also be related to comorbidities, e.g. sleep disordered breathing in obese patients and those with Down syndrome, restrictive lung defects in cyanotic patients with skeletal abnormalities, epileptic fits in patients with current or prior cerebral abscesses. In ES, many of the signs and symptoms relate to the long-standing cyanosis, which is exacerbated by exertion. Digital clubbing is often present and differential cyanosis and/or clubbing (limited to the lower extremities) occurs in patients with ES and large PDAs. Hyperviscosity symptoms may occur in cyanotic patients with a compensatory erythrocytosis, but they are rare in everyday clinical practice. Moreover, iron deficiency can cause hyperviscosity-like symptoms, including headache, irritability, paraesthesia, and exercise intolerance [17].

In all patients with a suspicion of PAH-CHD, taking a careful history is important, focusing on the type and timing of previous surgeries or interventions, and on comorbidities. The physical examination is important to identify signs of PH (e.g. a prominent 2nd heart sound, a pan-systolic murmur of tricuspid regurgitation and a diastolic murmur of pulmonary regurgitation), signs of coexisting cardiac lesions (e.g. the murmurs of pulmonary stenosis or left atrioventricular valve regurgitation) or other conditions (e.g. obesity, diabetes, systemic hypertension) that may contribute to the development of PH.

The diagnostic workup should include pulse oximetry on fingers and toes, 12-lead electrocardiography (ECG), chest radiography, pulmonary function testing, and blood testing (including full blood count, renal and liver function, thyroid function, uric acid, brain natriuretic peptide or NT pro-BNP and iron studies, including ferritin and transferrin saturations). Echocardiography should also be performed in all patients, and a decision should be made on whether to proceed to cardiac catheterisation (RHC) [5,18–20].

Diagnostic work-upElectrocardiography and chest radiography

An ECG can be useful in raising the suspicion of PH. In CHD, ECG changes related to the underlying defect or resultant physiological manifestations may also signify PH: High P wave amplitude (‘P pulmonale'), rightward QRS axis, bundle branch block, high amplitude ECG voltage or signs of right ventricular dominance (Figure 1). When present on ECGs of CHD patients, these changes can masquerade as PH may mask evolving PH. Expert evaluation and comparison with previous ECGs is required to pick up subtle ECG changes over time. Features on an ECG can also provide information regarding the underlying diagnosis in ES. For example, left axis deviation with a first-degree AV-block in an ES patient (especially in the presence of Down syndrome) is likely to be associated with a complete atrioventricular septal defect rather than an isolated VSD. Finally, the ECG can detect arrhythmias, which are common in PAH-CHD [21] and, without early identification and treatment, can easily lead to decompensation in patients with PH [22].

Chest radiography provides a wealth of information in patients with CHD, including clues about visceral and atrial situs (the latter related to the type and position of the morphologic main bronchi), position of the heart and rib abnormalities (e.g. the absence of the 12th rib is typical of Down syndrome). Information about the heart structures can also be gleaned from the chest radiogram. Cardiomegaly is often absent in patients with ES who have a well-adapted, hypertrophied but not a significantly dilated RV, reflecting the absence of a significant shunt. However, pulmonary arterial dilatation is typically present, and is often severe, associated with calcification of the central pulmonary arteries in older patients. Peripheral pruning, i.e. the prominence of central pulmonary arteries with disproportionately small peripheral arteries, is also a sign of a severely elevated PVR. Calcification at the area of a PDA is often seen in ES patients, signifying a large duct.

The chest radiograph is also helpful in detecting the pulmonary vascular pattern. Pulmonary venous congestion is indicated by prominent upper lobe vessels in patients with left heart disease. Increased vascularity is suggestive of pulmonary plethora, as is seen in patients with a significant systemic-to-pulmonary shunt. Pleural effusions or consolidation, as in the presence of a lower respiratory tract infection or haemoptysis, can also be seen. Other useful information derived from the chest radiograph includes signs of prior surgery, thoracic skeletal abnormalities (e.g. scoliosis), parenchymal lung disease (e.g. lung fibrosis, bronchopulmonary dysplasia), which may prompt further investigations.

Echocardiography and cardiac magnetic resonance imaging

Echocardiography is essential is identifying PH in CHD patients and drives the clinical decision to proceed to cardiac catheterisation. Current guidance focuses on the use continuous wave Doppler measurement of peak tricuspid regurgitation velocity (TRV), combined with other echocardiographic signs of PH (related to the ventricles, pulmonary artery, inferior vena cava and right atrium) and the overall clinical suspicion (Figure 2) [2,23]. However, in patients with more complex CHD (e.g. patients with a systemic RV, pulmonary stenosis or pulmonary atresia) or other coexisting lesions (Figure 3) [19] significant expertise is required, always remembering that the diagnosis of PH is best established through cardiac catheterisation [24]. A detailed overview of the role of echocardiography in identifying CHD patients with PAH is provided by Dimopoulos et al. [19].

Cardiac magnetic resonance imaging (MRI) plays an important role in the diagnosis of PAH-CHD. It should be routinely used in all patients to identify intra- and extracardiac defects that may not be detected in transthoracic echocardiography (e.g. partial anomalous pulmonary venous return, sinus venosus defects, large PDAs in Eisenmenger patients etc.), especially in adult patients with limited echocardiographic windows. Moreover, cardiac is able to provide reliable estimates of pulmonary and systemic blood flow (QP and QS) and is used in some centers during cardiac catheterization (hybrid catheter labs), limiting the error relating to the Fick method. It can also provide estimates of pulmonary vascular compliance and pulsatility, hence providing better characterization of the pulmonary vascular bed compared to PVR alone.

Right heart catheterisation

RHC is required for the accurate diagnosis and classification of PH. Additionally, RHC, provides valuable prognostic information and guides decision-making regarding the operability of congenital defects. In CHD, precise calculation of PVR is essential, as PH may be partially or entirely related to increased pulmonary blood flow (significant systemic-to-pulmonary shunting). An accurate estimation of PVR depends heavily on the method used to estimate pulmonary blood flow: The direct Fick method (in which oxygen consumption is measured at the time of cardiac catheterisation) or MRI measurement of pulmonary blood flow (in a hybrid catheter lab) are the most accurate. Thermodilution should be avoided in the presence of intracardiac shunts.

While cardiac output (or QP and QS in patients with shunts) and PVR should ideally be indexed in all patients to account for age and body habitus, there are significant complexities in its interpretation. PVR indexed (PVRi) is calculated by multiplying PVR by body surface area (BSA). For example, tall overweight individuals with a normal PVR may have a raised PVRi due to a high BSA. Whether the BSA used for such calculations should be estimated based on lean mass remains a matter of debate. Significant expertise in PAH, CHD and invasive haemodynamics is required when interpreting clinical data and applying guidance on the operability of congenital defects in patients with PAH.

One notable pitfall of marked significance in our erythrocytotic cohort is the dependence of accurate PVR measurement on blood viscosity, and thus on the haemoglobin level. A recent study by Kempny et al. looking at 465 patients with pulmonary hypertension found a clinically significant difference between measured PVR and PVR corrected for haemoglobin level (“viscosity-adjusted PVR”) [25], with significant overestimation of PVR without correction in erythrocytotic patients.

RHC is not associated with significant risks in the overall PH population, but ES patients may be at increased risk of paradoxical embolism and are more prone to arrhythmias. Moreover, approximately a third of ES patients have Down syndrome, most of whom require sedation or general anaesthesia to undergo invasive procedures, both of which carry significant risks in ES and may influence haemodynamics. For this reason, in contemporary practice, many expert centres opt not to proceed to RHC in many adult ES patients with large post-tricuspid shunts. A low velocity bidirectional shunt across a large VSD in a cyanotic patient is highly suggestive of near-equal pressures between the 2 ventricles. In the absence of pulmonary stenosis, PA pressures must be at systemic levels. Similarly, low-velocity bidirectional flow across a large PDA is a sign of near-equal pressures between the PA and aorta, which, in the presence of cyanosis in the lower extremities, is highly suggestive of ES. Cardiac magnetic resonance can be helpful in this setting, by confirming the absence of a large systemic-pulmonary shunt, hence supporting the fact that the rise in PA pressures detected on echocardiography is due to a rise in PVR, rather than an increase in pulmonary blood flow.

PAH-CHD patients with systemic-pulmonary shunts (group B in the PAH-CHD classification) may be amenable to surgery or intervention to repair the defect. Current international PH guidelines recommend that patients with a (practically normal) PVRi <4 WU.m2 can undergo repair of their defect, whereas repair should be avoided in those with a PVRi >8 WU.m2. In the latter, PVD is likely to be established and may progress after defect repair [2]. Patients with a PVRi between 4-8 WU.m2, fall into a “grey zone” of uncertainty, and the decision to attempt defect repair should be made on an individual-case basis in an expert centre with multi-disciplinary input (Figure 4). The above hemodynamic criteria differ to those of the AHA/ACC and ESC ACHD guidelines, reflecting a lack of evidence in the literature [26,27]. Recent AHA/ACC guidelines recommend that patients with ventricular level, systemic-to-pulmonary shunts should undergo surgical or device closure if the shunt is haemodynamically significant (LV enlargement, QP:QS≥1.5:1) with a pulmonary artery systolic pressure (PASP) <50% of systemic pressure and a PVR <1/3 of systemic vascular resistance (Class I indication). Repair should still be considered in the absence of a haemodynamically significant shunt where there is progressive aortic regurgitation (Class IIa) or a personal history of infective endocarditis (Class IIb). In patients with secundum ASDs, the same PASP and PVR cut-offs should be present along with right heart enlargement and QP:QS≥1.5:1 to support closure, with functional impairment (Class I) and without (Class IIa).

Closure is not recommended and may be harmful in patients with a PASP greater than 2/3s systemic pressure, a PVR of >2/3 systemic or a net pulmonary-to-systemic shunt in all types of shunt. Cases where the haemodynamic parameters fall between these cut-offs (PASP or PVR between 1/3 and 2/3 systemic levels) should undergo expert ACHD and PH assessment. The effectiveness of surgical or device closure remains unclear in this subgroup of patients with pre- and post-tricuspid shunts (class IIb) (Figure 4).

The cut-offs used in the guidelines remain largely arbitrary and should be used in combination with other clinical information. Neither haemodynamics nor lung biopsy can accurately predict the potential of PVD to be reversed after corrective surgery or intervention [5,28,29] Patients with PAH persisting or presenting after CHD repair (group D in the PAH-CHD classification)[2] have the worse prognosis of all PAH groups in contemporary cohorts, which warns against closing defects in patients with established PVD. [30]

Comorbidities and complications

Eisenmenger syndrome is a multisystem disorder, resulting from the combination of the congenital heart defect, PH, long-standing cyanosis and a chronically low cardiac output. Heart failure, renal failure and hepatic dysfunction are common in ES and are associated with an increased risk of death. Complications such as pulmonary artery dilatation and in situ thrombosis are frequently encountered in ES and are associated with cardiac arrhythmias [1,31,32]. Pregnancy is contraindicated and dual contraception is recommended where appropriate [22,33,34].

Chronic cyanosis contributes to the significant exercise intolerance and ventilatory inefficiency encountered in ES [35]. It also promotes secondary erythrocytosis, an appropriate compensatory response to hypoxia through an erythropoietin-mediated increase in haemoglobin concentration and haematocrit. This results in an increased oxygen carrying capacity and, thus, improved oxygen delivery to the peripheral tissues. Unlike primary erythrocytosis (including polycythaemia vera), secondary erythrocytosis is not characterised by a significant risk of thromboembolic events, and rarely leads to hyperviscosity symptoms in well-hydrated, iron replete patients. Venesections to maintain a haematocrit level within an arbitrary predetermined level (haematocrit <65%) are not indicated and may be associated with a higher risk of cerebrovascular events [36]. The indications for venesection are few (Table 4). On the other hand, iron deficiency is very common in ES and “relative anaemia”, i.e. a haemoglobin concentration lower than expected for the severity of cyanosis, can be detrimental. As the degree of hypoxia worsens, the haemoglobin level is expected to increase, and Broberg et al. have suggested that the optimal haemoglobin level can be estimated using the following equation:

Predicted haemoglobin (g/dL) = 57.5 – (0.444 x oxygen saturation(%)) [37].

The authors of this paper suggest that a patient with resting oxygen saturations of 80% is expected to have a haemoglobin level of 22.91.5 g/dL.

All cyanotic patients should be screened for iron deficiency anaemia with iron studies. Ferritin concentration <30 µg/L, or a ferritin <50 µg/L and transferrin saturations <20% may be used to identify iron deficiency in this group of patients, although robust cut-offs are lacking. While transferrin receptor levels are felt to be the most reliable method for detecting iron deficiency, these are not widely available in clinical practice. MCV is not reliable in this setting.

In cases of iron deficiency, iron supplementation is recommended while monitoring for excessive erythrocytosis or thrombocytopenia, especially in patients with Down syndrome (Table 3) [5,10]. Intravenous iron supplementation has been used safely in this population [38], although the dosing regimen and approximate target haemoglobin are yet to be validated.

Other complications of cyanosis include a predisposition to both bleeding (e.g. haemoptysis, epistaxis, menorrhagia, etc.) and thrombotic complications, and to gout. The latter is caused by the tendency of cyanotic patients for high uric acid levels, related to the high red cell count. Eisenmenger patients often present with gout, which can be severely debilitating and at times difficult to control. Interestingly, high levels of uric acid have been found to relate to mortality in Eisenmenger patients [39].

The presence of a pulmonary-to-systemic shunt also predisposes patients to major paradoxical embolic complications. Cerebral abscess is a feared, life-threatening, complication that can occur in the presence or absence of endocarditis. International guideline recommendations for endocarditis prophylaxis around high-risk dental procedures in cyanotic CHD patients are aimed at minimising the risk of such devastating infective disease [40].

Adult survivors with ES appear to have a significantly better prognosis compared to other types of PAH, e.g. idiopathic PAH. The reason for this is thought to be the long-term adaptation of the right ventricle to a high afterload, observed in many but not all patients with post-tricuspid defects. Such adaptation is less obvious in ES patients with a pre-tricuspid shunt (atrial septal defect) and in patients with repaired CHD.[16] Despite this, mortality and morbidity is high in ES and is often related to complications related to low respiratory tract infections, bleeding, arrhythmia, non-cardiac surgery, embolic events and heart failure [41,42]. Several markers of prognosis have been reported for ES, including BNP, 6MWT distance, renal function and albumin concentration [15,43,44]. A recent large multicenter study identified the following multivariable predictors of outcome: age, presence of a pre-tricuspid shunt, pericardial effusion, resting oxygen saturation and the absence of sinus rhythm [45]. Little is known on how to predict outcome in non-ES PAH-CHD.

Management strategies

The aims of treatment in ES are multiple and include the improvement of exercise tolerance, quality of life and longevity [46,47]. Supportive measures are the mainstay of care for ES patients, with an aim of reducing symptoms and treating or preventing complications related to hypoxaemia, hematological or coagulation disorders, congestive cardiac failure, rhythm disturbances and infection. Attention is required when assessing coagulation parameters in cyanotic patients, as secondary erythrocytosis increases hematocrit and decreases plasma volume (the use of citrate-adjusted blood bottles is required). Anticoagulation remains controversial in ES syndrome, due to the increased risk of thrombosis, but also bleeding. Hence, neither anticoagulants nor antiplatelets are routinely prescribed in ES, unless there are specific indications (arrhythmias, embolic events etc.). Non-vitamin K anticoagulants have not been tested in this group, and there are still concerns regarding the limited availability of direct reversal agents [48].

Diuretics are widely used in ES patients presenting with congestive heart failure, including loop diuretics and spironolactone. Special care should be taken when using diuretics to avoid dehydration, which may trigger hyperviscosity symptoms or cause an excessive reduction in RV preload. Moreover, renal dysfunction is common in ES and may be exacerbated by diuretics, other nephrotoxic medication or the use of contrast agents during diagnostic and/or interventional procedures [49].

Nowadays, PAH therapies are routinely prescribed in patients with ES, especially in those who are in functional class 3 or above (who are the vast majority when interrogated carefully), aiming at an improvement in exercise capacity, functional class and prognosis [50–52]. PAH therapies target three pathophysiological pathways in PAH: the prostacyclin, nitric oxide, and endothelin pathways. The BREATHE-5 study was the first multi-centre, randomized, double-blind, placebo-controlled trial in patients with ES. Bosentan was safe and improved exercise capacity and cardiopulmonary hemodynamics, with effects sustained up to 1 year in the open-label extension study (40 week follow-up), in WHO class III ES patients [50,53]. Other smaller randomized and non-randomised studies have reported on the beneficial effects of other PAH therapies, including tadalafil, sildenafil and prostanoids in ES [51,54–57]. Intravenous prostanoids are used in ES patients, even though there are concerns about line infection predisposing to endocarditis and enhanced systemic side-effects due to the drug shunting to the systemic circulation. Recently, the MAESTRO trial on PAH therapy with macitentan in Eisenmenger patients was published. This was the largest randomized trial performed in ES to date. The primary endpoint was not met as there was an improvement in 6-minute walk distance both in the macitentan but also, surprisingly, in the placebo arm. However, a significant improvement was reported in PVR and BNP levels [58]. The use of calcium channel blockers is discouraged in ES, as they may cause significant peripheral vasodilatation and hypoxaemia.

PAH therapies are also used in repaired PAH-CHD patients (Group D), who have been included in many of the large randomized trials with other PAH groups, mainly idiopathic and connective tissue related PAH [59–62]. Even though most of these trials were not powered to assess the efficacy of therapy on the CHD subgroup, it is felt that the indication for treatment expands to this group. Patients belonging to group C of the PAH-CHD classification (small and hemodynamically irrelevant cardiac defects) should be diagnosed as PAH with additional cardiac defect and treated like idiopathic PAH. Finally, as mentioned earlier, PAH-CHD patients with systemic-to-pulmonary shunts (group B) may benefit from repair of their defect, depending on haemodynamics. PAH therapies have also been used in patients deemed inoperable and those in whom PAH persists after repair. Optimisation of haemodynamics with PAH therapies prior to defect repair (a “treat-and-repair approach”) in patients with borderline or “prohibitive” haemodynamics remains controversial and should only be considered in well-selected patients followed in expert centers [26,63,64]. Recent AHA/ACC guidelines on grown up congenital heart disease (GUCH) suggest that patients denied ASD closure due to severe PAH may become candidates for closure by using “PA vasodilators and remodeling therapy with prostaglandins, endothelin blockers, and PDE-5 inhibitors” [27]. For adult patients with a VSD and PAH, it is suggested that a subgroup “may benefit from closure of the VSD if the net shunt is left-to-right either at baseline or with PAH therapies”. They also suggest that, in theory, treatment of these patients with PAH therapies before closure could improve outcomes. It should be noted that there is little evidence to support a significant long-standing remodeling effect on the pulmonary vasculature of PAH therapies, or the pre-operative use of PAH therapies, and hence extreme caution is necessary when taking this approach. In borderline cases in which the decision is made to close a large defect, the use of a fenestrated device or surgical patch may allow decompression of the RV [27].

The only definitive treatment for ES is lung transplantation with shunt closure or combined heart-lung transplantation (HLT) [65]. Even though it has been suggested that patients with ES may have a better post-transplantation prognosis than patients with idiopathic PAH or other types of congenital heart defects, few adult ES patients are listed. The timing of transplantation is exceptionally delicate as most patients remain clinically stable for decades (albeit with an underlying multi-system disorder), but have developed overt multi-organ failure by the time they are eligible for assessment by cardiovascular criteria [66,67]. Patients with repaired PAH-CHD are likely to deteriorate faster than ES patients and should be referred to transplantation early. However, prior surgery, including the presence of adhesions, allosensitisation due to prosthetic material and perioperative transfusions, anatomical considerations (e.g. anomalous venous return) and the need for HLT rather than lung-only transplantation present barriers to transplantation.

Conclusions

Despite major advances in our knowledge of ES and the availability of PAH therapies, patients with ES are still faced with significant morbidity and mortality. Moreover, little is known about the management of other types of PAH-CHD, including the assessment of operability and timing of corrective surgery in patients with CHD and various degrees of PAH. A multidisciplinary approach is required when managing PAH-CHD patients, combining expertise from PAH, CHD and other disciplines. Large multicentre registries and a protocolised management approach are urgently needed to improve our understanding and optimise outcomes in this complex population.

2

Expert Opinion

Over the last 2 decades, there have been major advances in our understanding and treatment of PAH-CHD. Over a century since Victor Eisenmenger’s description of this condition and half a century after its systematic description by Paul Wood, we only now have some evidence on which to base our management of this disease. While the number of Eisenmenger patients is decreasing in western countries [68] as a result of systematic screening of all newborns and early repair of CHD, ES is unlikely to disappear and will remain a major problem in developing countries. Investment is therefore required to build and maintain tertiary PAH-CHD centres, where the appropriate expertise can be concentrated to ensure high quality care of such complex patients.

Despite recent advances, there are large gaps in the evidence on important aspects of PAH-CHD management. Importantly, there is as yet little evidence to guide the haemodynamic cut-offs and other operability criteria to be used when assessing operability in PAH-CHD patients. Recent guidelines provide fairly arbitrary cut-offs and highlight the risks of repairing defects in patients with established PVD. As large randomised trials are unlikely to take place in this area, it is important that well-designed international registries are established aimed at answering important clinical dilemmas.

The availability of PAH therapies has revolutionised our approach to PAH-CHD, especially for patients with Eisenmenger syndrome and those with repaired defects. Most expert centers use such therapies routinely as monotherapy or in combination, with the addition of parenteral therapies when appropriate. Despite the relatively limited evidence in this population, it is now widely accepted that PAH therapies are able to improve the quality of life and survival of Eisenmenger patients and should be prescribed early, before major clinical deterioration occurs. However, financial and other restraints have limited the use of such therapies in non-Western countries, where the majority of Eisenmenger patients live. Efforts should be made to make such therapies available world-wide and train local experts in their use.

Even in Western countries, many PAH-CHD patients remain undiagnosed and do not benefit from specialist care. Patients who underwent CHD repair decades ago were deemed “cured” and were often discharged from specialist CHD care. We now know that no CHD patient is completely “cured”, and many repaired patients present with late complications, including PAH. Many adult patients with Eisenmenger syndrome were lost to follow-up after being told that no treatment was available for their condition decades ago. Life-long specialist care is essential for all CHD patients.

Within the coming decade, an increasing number of patients will benefit from expert care and appropriate treatment with PAH therapies. The future of research in this area lies in collaboration studies, aimed at understanding optimal treatment and identifying new diagnostic protocols, risk stratification scores and therapeutic avenues [69]. Initiatives, such as the UK-based CHAMPION (Congenital Heart disease And pulMonary arterial hyPertension: Improving Outcomes through education and research Networks) are best placed in promoting education and research in this area, in collaboration with patient associations and industry [19,32,70]. International collaboration studies, such as the MUSES study by Kempny et al., are necessary to achieve adequate sample size and answer important clinical hypotheses, while making the results of research relevant and applicable worldwide [42,45].

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Reference annotations

‘*’ – of interest.

‘**’ – of considerable interest.

[2] Galiè N, Humbert M, Vachiery J-L, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertensionThe Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur. Heart J. 2016;37:67–119.

**Current European pulmonary hypertension guidelines, which include a classification of and recommendations for congenital heart disease-related pulmonary hypertension.

[5] Dimopoulos K, Wort SJ, Gatzoulis MA. Pulmonary hypertension related to congenital heart disease: a call for action. Eur. Heart J. 2014;35:691–700.

*A concise review of PAH-CHD through 10 “action points” to be taken to optimize outcomes, avoid common pitfalls and old practices.

[12] Zhu N, Welch CL, Wang J, et al. Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease. Genome Med. 2018;10:56.

*The recent discovery of a candidate risk gene (SOX17) associated with PAH-CHD progresses the theory of a genetic substrate, explaining some of the heterogeneity in the development of PAH.

[19] Dimopoulos K, Condliffe R, Tulloh RMR, et al. Echocardiographic Screening for Pulmonary Hypertension in Adults with Congenital Heart Disease. J. Am. Coll. Cardiol. 2018;

**A recent, expert opinion paper and systematic review, which fills the gap in the recommendations with respect to the echocardiographic signs of PH in CHD patients, focusing on a range of simple and complex types of CHD.

[26] Baumgartner H, Bonhoeffer P, De Groot NMS, et al. ESC Guidelines for the management of grown-up congenital heart disease (new version 2010). Eur. Heart J. 2010;31:2915–2957.

**The European Society of Cardiology guidelines for the management of ACHD patients from 2010, with specific cut-offs for intervention in ASD, VSD and AVSD (see 2018 AHA update) and a section on Eisenmenger syndrome and severe PAH-CHD.

[27] Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 2018;

**The 2018 American Heart Association/American College of Cardiology guidelines for the management of ACHD patients, with updated guidelines for the assessment and operability of congenital defects associated with PAH.

[50] Galiè N, Beghetti M, Gatzoulis MA, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation. 2006;114:48–54.

*The first large, multi-centre, randomized, double-blind, placebo-controlled trial in patients with Eisenmenger syndrome. Oral bosentan therapy improved exercise capacity and haemodynamics at 16 weeks.

[58] Gatzoulis MA, Landzberg M, Beghetti M, et al. Evaluation of Macitentan in Patients With Eisenmenger Syndrome. Circulation. 2019;139:51–63.

*A recent multi-centre, double-blind, randomized, placebo-controlled, 16-week trial evaluating the efficacy and safety of macitentan in patients Eisenmenger syndrome. Macitentan did not show superiority over placebo in change in exercise capacity, although it was well tolerated and showed a significant improvement in NT-pro BNP levels and PVRi.

Tables:

Table 1. Clinical classification of pulmonary arterial hypertension associated with congenital heart disease according to current European pulmonary hypertension guidelines.

A) Eisenmenger syndrome

B) PAH associated with prevalent systemic-to-pulmonary shunts

Includes all large intra- and extra-cardiac defects which begin as systemic-to-pulmonary shunts and progress over time to a severe rise in PVR and shunt reversal (pulmonary-to-systemic) or bidirectional shunting; cyanosis, secondary erythrocytosis, and multiple organ involvement is typically present.

Moderate to large defects with PVR mildly to moderately increased. There is systemic-to-pulmonary shunting and no cyanosis at rest. THe defect can be:

· Correctable defect: with surgery or percutaneous procedure.

· Non-correctable defect: PVR is too high

C) PAH with small/coincidental defects

D) PAH after defect correction

Marked elevation in PVR in the presence of small cardiac defects (e.g. ventricular septal defects <1 cm and atrial septal defects <2 cm in effective diameter assessed on echocardiography) which do not account for the elevated PVR; the clinical picture is similar to idiopathic PAH. Closing the defect is usually contra-indicated.

Congenital heart disease is repaired, but PAH either persists immediately after correction or recurs/develops months or years after correction, in the absence of significant residual haemodynamic lesions. These patients have been included in large trials of PAH therapy with other types of PAH (e.g. idiopathic).

Abbreviations: ASD, atrial septal defect; PAH, pulmonary arterial hypertension; PVR, pulmonary vascular resistance; VSD, ventricular septal defect.

Table 2. Heath-Edwards histopathologic classification of Pulmonary Hypertension. A description of six grades of structural changes in the pulmonary arteries.

GRADE I

Hypertrophy of the media of small muscular arteries and arterioles.

GRADE II

Intimal cellular proliferation in addition to medial hypertrophy.

GRADE III

Advanced medial thickening with hypertrophy and hyperplasia, including progressive intimal proliferation and concentric fibrosis. Obliteration of arterioles and small arteries.

GRADE IV

“Plexiform lesions'’ of the muscular pulmonary arteries and arterioles with a plexiform network of capillary-like channels within a dilated segment.

GRADE V

Complex plexiform, angiomatous and cavernous lesions and hyalinization of intimal fibrosis.

GRADE VI

Necrotizing arteritis.

Table 3. Hyperviscosity symptoms

Intra-cranial / neurological

Extra-cranial

Hearing loss

Epistaxis

Headaches

Rectal bleeding

Paraesthesia

Menorrhagia

Vertigo

Persistent bleeding from cuts

Ataxia

Prolonged bleeding following minor procedures

Blurred vision

Complete loss of vision

Seizures

Somnolence progressing to stupor and coma

Table 4. Indications for venesection:

Indications for venesection in patients with Eisenmenger syndrome

Moderate-to-severe hyperviscosity symptoms and significant secondary erythrocytosis (Haemoglobin concentration >23-24 g/dL) in the absence of volume depletion or dehydration.

Preoperatively for autologous blood donation if the haematocrit level is >65% and for boosting platelet production.

Figure Legends

Figure 1. Electrocardiogram shows sinus rhythm 70 bpm with a first-degree atrioventricular block with (PR interval of 200ms), right ventricular (RV) hypertrophy and right bundle branch block. Signs of right atrial dilatation with widespread ST-T wave changes.

Figure 2: Echocardiogram of an ES patient with a large ASD. There is a dilated pulmonary artery (A, arrow), with moderate pulmonary regurgitation and moderate tricuspid regurgitation (B). There is a hypertrophied right ventricle (C) and the gradient of the tricuspid regurgitation (D) suggests severe pulmonary hypertension is present.

Figure 3. Echocardiography in an Eisenmenger patient with a large perimembranous VSD (arrow). In (a), the large VSD (arrow) is visible between the left ventricle (LV) and the hypertrophied right ventricle (RV) in a 5-chamber view. In (b), parasternal long axis view showing low velocity right-left shunting through the VSD (arrow). In (c), Doppler interrogation of the shunt demonstrates that it is actually bidirectional, depending on the phase of the cardiac cycle. In (d), a short pulmonary valve acceleration time is shown.

Figure 4. Clinical decision tree with PVR cut-offs when considering repair in patients with PAH-CHD, adapted from references [2,26].

Abbreviations: (A)CHD = (adult) congenital heart disease; ASD = atrial septal defect; ES = Eisenmenger syndrome; LV = left ventricular; PAH = pulmonary arterial hypertension; PASP pulmonary arterial systolic pressure; PH = pulmonary hypertension; PVD = pulmonary vascular disease; PVR = pulmonary vascular resistance, PVRi, = pulmonary vascular resistance index; QP:QS = pulmonary flow: systemic flow; WU = Wood units.

Figure 1

Figure 2

Figure 3

Figure 4

34

ID: Y92-04226

24/02/1950 65 year(s)

Female

Referring:

Technician:

Confirmed By:

05/02/2016 11:41:21 Previous ECG: 12/12/2014 13:59:40

HR: 69PRdQRSQTQTcPAxQrsAxTAx

= 198 ms = 148 ms = 404 ms = 423 ms = 74 = 105 = -76

12-SL ECG

Unconfirmed

JOLLY JANE CHRISTINE

25 mm/sec 10 mm/mV F: -1 Hz W: -0.01--1 Hz Mckesson - MIG25 mm/sec 10 mm/mV F: -1 Hz W: -0.01--1 Hz Mckesson - MIG

Unknown

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

European PH guidelines

American ACHD guidelines

Surgical or device closure (Class I if post-tricuspid shunt or ASD

with functional impairment)

Degree of PVD

PVR ⅓ - ⅔ systemicAND/OR

PASP ½ - ⅔ systemic

PVR < ⅓ systemicAND

PASP < ½ systemic

PVR > ⅔ systemicAND/OR

PASP > ⅔ systemic

Borderline PVRPVRi 4 – 8 WU.m2

No PAHPVRi < 4 WU.m2

Severe PAHPVRi >8 WU.m2

“Grey zone”Individual patient

evaluation at a tertiary centre (Class IIb)

No closure (class III: harm)

Surgical or device closure

“Grey zone”

No closure

Left-to-right

Right-to-left (e.g. ES)

Shunt direction

Haemodynamic significance of shunt

QP:QS ≥ 1.5:1AND

LV enlargement (post-tricuspid) orRight heart enlargement (ASD)

QP:QS < 1.5:1OR

Normal heart size

Consider coincidental PAH (group 3 PAH-CHD) and other clinical indications for closure

e.g. history of endocarditis

CHD with prevalent systemic-to-

pulmonary shunts

Ventricular level shunt (post-tricuspid) or ASD (pre-tricuspid)