Pulmonary hypertension in adults with congenital heart disease: Disease-specific management

INTRODUCTION — Approximately 3 to 10 percent of patients with congenital heart disease (CHD) develop pulmonary hypertension (termed pulmonary hypertension-congenital heart disease [PH-CHD]) [1,2]. (See "Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis", section on 'Epidemiology'.)

Disease-specific management, shunt closure, and transplantation for adults with PH-CHD are discussed here. The clinical manifestations, diagnosis, general management, and prognosis of PH-CHD are discussed separately. (See "Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis" and "Pulmonary hypertension in adults with congenital heart disease: General management and prognosis".)

DEFINITIONS

●Pulmonary hypertension (PH) – PH is defined as a mean pulmonary artery pressure (PAP) >20 mmHg at rest [3]. This threshold for diagnosis is lower than the previously used threshold of ≥25 mmHg [4].

●Pulmonary hypertension-congenital heart disease (PH-CHD) – Patients with PH-CHD have a variety of types of PH (table 1). In patients with PH-CHD, PH is commonly but not always caused by CHD. The most common type of PH-CHD is congenital shunt-related pulmonary arterial hypertension (PAH). (See "Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis", section on 'Classification' and "Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis", section on 'Pathogenesis'.)

●Pulmonary arterial hypertension (PAH) – PAH is a type of PH diagnosed by demonstration of a mean PAP ≥20 mmHg and a pulmonary vascular resistance (PVR) ≥2 Wood units (WU), along with exclusion of other types of PH (table 1). This definition of >2 WU was revised from >3 WU in the 2022 European Society of Cardiology/European Respiratory Society guidelines to reflect data regarding the prognostic significance of PVR >2 WU [5]. However, for treatment purposes, PVR >3 WU is utilized since data regarding utility of treatment for PVR 2 to 3 WU are not available. Severe PAH is identified by a PVR ≥5 WU [6]. PAH associated with CHD (PAH-CHD) is one of many types of PAH. Eisenmenger syndrome is the most severe form of congenital shunt-related PAH. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Group 1: Pulmonary arterial hypertension'.)

●Eisenmenger syndrome – This disorder is the most severe form of congenital shunt-related PAH and is characterized by the triad of large intra- or extracardiac defect with an initial systemic-to-pulmonary shunt (ventricular, atrial, or great artery (table 2)), PAH with shunt reversal (right-to-left) or bidirectional shunting, and resulting hypoxemia with cyanosis (figure 1A-B) [7,8]. The pulmonary arterial disease in Eisenmenger syndrome is caused by increased pulmonary blood flow and/or elevated PAP.

OVERVIEW — Disease-specific therapy includes primary therapy directed at the underlying cause of PH and therapy directed at the pathophysiologic process (eg, pulmonary arterial hypertension [PAH]). Disease-specific therapy differs among the various causes and groups of PH (table 1) and is administered along with general management of PH-CHD, as discussed separately. (See "Pulmonary hypertension in adults with congenital heart disease: General management and prognosis".)

●Group 1 – Most patients with PH-CHD have group 1 PH (PAH). For patients with group 1 PH, there is generally no effective therapy for the underlying cause of PAH, and PAH-specific therapy is directed at PAH itself. (See 'PAH-specific therapy' below.)

●Group 2 – For patients with group 2 PH (PH due to left heart disease), the mainstay of treatment is optimized management of the underlying left heart disease (eg, heart failure, mitral valve disease, or aortic valve disease). (See "Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults", section on 'Management'.)

●Group 3 – For patients with group 3 PH (PH due to lung disease and/or hypoxia), management includes treatment of the underlying condition (ie, cause of hypoxemia) and correction of hypoxemia with supplemental oxygen. Patients with PH related to interstitial lung disease or combined pulmonary fibrosis and emphysema may benefit from therapy with inhaled treprostinil. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

●Group 4 – For patients with group 4 PH (chronic thromboembolic PH), therapy includes surgical thromboendarterectomy or, for inoperable chronic thromboembolic PH, PAH-specific therapy or pulmonary balloon angioplasty. (See "Chronic thromboembolic pulmonary hypertension: Pulmonary thromboendarterectomy" and "Chronic thromboembolic pulmonary hypertension: Pulmonary hypertension-specific therapy".)

●Group 5 – Patients with group 5 PH have a variety of disorders with unclear or multifactorial mechanisms for PH. Treatment is available for some of the causes of group 5 PH, such as sarcoidosis, vasculitis, and PH associated with myeloproliferative disorders. (See "Sarcoidosis-associated pulmonary hypertension: Treatment and prognosis in adults" and "Treatment of pulmonary sarcoidosis: Initial approach" and "Management and prognosis of cardiac sarcoidosis".)

PAH-SPECIFIC THERAPY — Pulmonary arterial hypertension (PAH)-specific therapy is widely accepted for use in selected patients with group 1 PH (table 1), but consensus on a therapeutic approach to PAH-specific therapy for PH-CHD with group 1 PH (PAH-CHD) is lacking. There is limited evidence on the use of PAH-specific therapy in patients with PAH-CHD and tremendous variability in the anatomy and hemodynamics among patients with PAH-CHD. Thus, considerable expertise is required to achieve optimal results when using PAH-specific therapy to treat PAH-CHD.

The medical treatment strategy for patients with PAH-CHD is mainly based on expert opinion rather than clinical trials [9]. Most pivotal trials of PAH medications in this population have included a small number of patients with fully repaired simple congenital defects, but have excluded patients with residual defects. Case series and the experience of expert centers have provided some support for the use of PAH therapies in PAH-CHD with residual defects.

Patient selection — Hemodynamic cardiac catheterization is required before deciding on PAH-targeted therapy for patients with PH-CHD, as noninvasive evaluation of PH has not been standardized for patients with CHD. (See "Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis", section on 'Confirmation of diagnosis'.)

●Group 1 – PAH-specific therapy is suggested in selected patients with group 1 PH (ie, PAH-CHD) (table 3).

Management of PH in patients with Fontan circulation is discussed separately. (See "Management of complications in patients with Fontan circulation", section on 'Pulmonary vasodilator therapy'.)

●Group 2 – By contrast, PAH-specific therapy is not routinely used to treat patients with group 2 PH (PH due to left heart disease) given risk of harm and lack of convincing evidence of benefit. (See "Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults", section on 'Targeted therapy for pulmonary hypertension'.)

●Groups 3, 4, or 5 – For patients with groups 3, 4, or 5 PH, PAH-specific therapy is used only after carefully weighing the potential risks and benefits on a case-by-case basis. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

The following concepts are useful in selecting candidates for PAH-specific therapy:

●Avoid with elevated left heart filling pressures – If left heart filling pressures are elevated, PAH-targeted therapy is generally contraindicated due to risk of aggravating pulmonary vascular congestion and hypoxemia. Thus, as noted above, PAH-specific therapy is generally avoided in patients with group 2 PH. (See "Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults", section on 'Targeted therapy for pulmonary hypertension'.)

●Indications with normal left heart filling pressures – In the presence of normal left heart filling pressures and elevated pulmonary vascular resistance (PVR), PAH-targeted therapy may be helpful in the following settings:

•Right heart failure – If elevated PVR appears to be contributing to right heart dysfunction either at rest or during activity, PH-targeted therapy may be helpful in alleviating dyspnea and right heart failure.

•Right-to-left shunt – In patients with elevated PVR and right-to-left shunt either at rest or during exercise, PH-targeted therapy may lessen the degree of shunt and improve hypoxemia and symptoms.

Agent selection

General approach — The approach to PAH-specific therapy for patients with PAH-CHD is generally similar to that for group 1 PAH. Sequential combination therapy is used in patients with PAH-CHD not meeting treatment goals [5].

Decisions regarding PAH-specific therapy are based upon a comprehensive assessment of risk (low, intermediate, or high) based on multiple clinical features, including World Health Organization (WHO) functional class (table 3 and table 4). (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Baseline risk assessment'.)

For patients with PAH-CHD with shunts, avoidance of central lines is of particular concern given the risks of paradoxical emboli and infectious complications. Accordingly, when parenteral therapy is indicated, subcutaneous treprostinil may be used to avoid use of an indwelling line.

Calcium channel blocker not used — A key difference between the management of PAH-CHD and that of idiopathic PAH is that calcium channel blockers are not used to treat PAH-CHD, and routine acute vasodilator testing is not used to guide use of calcium channel blocker therapy in patients with PAH-CHD [5]. An exception is that patients with PAH with small or closed congenital shunts may be candidates for acute vasodilator testing as a guide to calcium channel blocker therapy, as they may respond similarly to patients with idiopathic PAH [10].

As discussed below, acute vasodilator testing may be performed to guide decisions on whether to close shunt lesions in patients with PAH-CHD. (See 'Shunt closure' below.)

Effects in patients with PAH-CHD — Limited data are available on the efficacy of PAH-specific therapy for patients with PAH-CHD or Eisenmenger syndrome, and an impact on prognosis has not been established.

An effect of PH-specific therapy on survival has not been established. A single-center retrospective analysis with propensity score matching of 229 patients with Eisenmenger syndrome found a significant association between pulmonary vasodilator therapy (bosentan, sildenafil, or epoprostenol) and improved survival [11]. However, the presence of bias due to confounding variables cannot be excluded even with propensity score matching. A multicenter retrospective study including 1098 patients with Eisenmenger syndrome found that although PAH-specific therapy was a predictor of improved survival in a univariate Cox regression analysis, it did not remain a predictor of survival in a multivariate model [12].

Endothelin receptor antagonist — Endothelin-1-triggered smooth muscle constriction results in diffuse vasoconstriction in the pulmonary arterial bed in patients with PAH, including those who have PAH on the basis of PH-CHD and Eisenmenger syndrome. Thus, the use of PAH-specific therapy to promote pulmonary vasodilation in this clinical setting is conceptually appealing. Among the endothelin receptor antagonists, bosentan, a dual endothelin receptor antagonist, is approved in Eisenmenger patients who are functional class III or IV. Other endothelin receptor antagonists (eg, ambrisentan, macitentan) show favorable hemodynamic effects in patients with PH-CHD.

The clinical efficacy of endothelin receptor antagonist therapy for patients with Eisenmenger syndrome is uncertain, given conflicting results of two randomized trials:

●The MAESTRO trial evaluated endothelin receptor antagonist therapy in 226 patients with Eisenmenger syndrome with WHO functional class II to IV. Patients were randomly assigned to macitentan 10 mg once daily or placebo for 16 weeks [13]. Patients were aged ≥12 years old and had simple or complex congenital cardiac defects; patients with Down syndrome or background PAH therapy were eligible. The mean change in six-minute walk distance (6MWD) was not significantly improved in the macitentan group (18.3 versus 19.7 m in the placebo group). There was an unexpectedly large improvement in 6MWD in the placebo group. N-terminal pro-B-type natriuretic peptide levels were significantly decreased with macitentan versus placebo (ratio of geometric means 0.80; 95% CI 0.68-0.94); PVR also decreased. A hemoglobin decrease from baseline of ≥2 g/dL occurred in 36 percent of patients treated with macitentan versus 8.9 percent of patients receiving placebo. The results of the MAESTRO trial differ from those of the smaller Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) comparing bosentan and placebo [14]. Of note, the MAESTRO trial included a more heterogeneous study population than the BREATHE-5 trial.

●Support for bosentan therapy in selected patients with Eisenmenger syndrome comes from the BREATHE-5 trial, in which 54 treatment-naïve patients with WHO functional class III Eisenmenger syndrome with simple cardiac defects and without Down syndrome were randomly assigned to oral bosentan or placebo [14]. The 6MWD significantly improved (mean 53 m), PVR fell significantly by 472 dyn-s/cm⁵, and mean pulmonary artery pressure (PAP) fell by 5.5 mmHg with oral bosentan compared with placebo.

PDE-5 inhibitor — Phosphodiesterase-5 (PDE-5) inhibitors (sildenafil and tadalafil) show favorable functional and hemodynamic results in patients with PH-CHD, but limited studies are available [15]. A trial randomly assigned 28 patients with Eisenmenger syndrome in WHO functional class II or III to tadalafil or placebo for six weeks followed by a two-week washout period and crossover to the other drug [16]. There was a significant improvement in 6MWD (mean difference 35.4 m) and WHO functional class (mean 1.96 versus 2.12) with tadalafil compared with placebo. Tadalafil significantly decreased PVR with no significant change in systemic vascular resistance.

A single-center retrospective study of 121 patients with Eisenmenger syndrome found that sildenafil therapy was significantly associated with survival on multivariate analysis [17]. However, bias caused by residual confounding could not be excluded.

Combination endothelin receptor antagonist plus PDE-5 inhibitor — The efficacy of adding a PDE-5 inhibitor to an endothelin receptor antagonist is uncertain, as limited studies are available on combination therapy [18,19]. In a study of 21 patients with Eisenmenger syndrome, all patients were treated with bosentan for nine months [19]. Patients were randomly assigned to receive sildenafil or placebo for three months, and a crossover was performed for the last three months. An improvement in 6MWD and reduction in PVR were observed with bosentan therapy, although there was no control group for this part of the study. The addition of sildenafil to bosentan did not significantly improve the 6MWD (21 versus 8 m with placebo) but significantly improved systemic oxygen saturation at rest (+2.9 versus -1.8 percent with placebo). The evidence for the combination of PDE-5 inhibitor and endothelin receptor antagonist in other forms of PAH is very strong, which may provide some additional rationale for this approach in PH-CHD. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Combination oral therapy'.)

Prostacyclin pathway agonists — Small observational studies suggested improvement compared with baseline assessment in patients with Eisenmenger syndrome on exercise tolerance and PAP with long-term use of prostacyclin analogs epoprostenol or treprostinil [20-23]. Small observational studies also suggested improvement compared with baseline assessment in exercise tolerance with iloprost therapy, though PAP was not significantly changed [21,22].

Selexipag is an oral prostacyclin receptor (also called IP-receptor) agonist. The IP-receptor is one of five types of prostanoid receptors. Selexipag is approved by the US Food and Drug Administration for treatment of group I PAH, including repaired PH-CHD [24]. Its use in other PH-CHD contexts remains to be explored, though it is anticipated that some patients with PH-CHD with residual shunt may benefit, with careful attention to effects on systemic blood pressure and degree of hypoxemia.

Guanylate cyclase stimulator — Riociguat, a soluble guanylate cyclase stimulator, showed favorable effects in the subgroup of patients with PAH associated with fully repaired CHD enrolled in the pivotal Pulmonary Arterial hyperTENsion sGC-stimulator Trial (PATENT) study [25]. Although there are no randomized data for riociguat use in patients with PH-CHD, it is anticipated that some such patients may benefit, with careful attention to potential side effects (systemic hypotension and worsening hypoxemia). Riociguat should not be used in combination with a PDE-5 inhibitor due to risk of hypotension or syncope.

SHUNT CLOSURE — The role of surgery or device closure of the shunt for the patient with PH-CHD depends on the underlying lesion, pathophysiology, and degree of pulmonary vascular disease. Reversible causes of PH should be sought and corrected. Standard recommendations for shunt closure are applied for patients with an atrial septal defect, ventricular septal defect or patent ductus arteriosus, as discussed separately. (See "Management of atrial septal defects in adults", section on 'Indications' and "Management and prognosis of congenital ventricular septal defect in adults", section on 'Indications for VSD closure' and "Management of patent ductus arteriosus (PDA) in term infants, children, and adults", section on 'Indications for closure'.)

For large defects

With left-to-right shunt — Indications for shunt closure in patients with or without PH are discussed separately:

●(See "Management of atrial septal defects in adults", section on 'Indications'.)

●(See "Management and prognosis of congenital ventricular septal defect in adults", section on 'Indications for VSD closure'.)

●(See "Management of patent ductus arteriosus (PDA) in term infants, children, and adults", section on 'Indications for closure'.)

With right-to left shunt — Surgical or percutaneous intervention for shunt closure is contraindicated in patients with Eisenmenger syndrome, as this is not generally beneficial and may be detrimental.

For small defects — Patients with elevated pulmonary vascular resistance and a small atrial septal defect or residual/recurrent shunt following closure require specialty care at an experienced center. Closure of the defect is generally discouraged since it acts as a "pop-off" valve for the right heart, allowing right-to-left shunt flow, offloading the right ventricle, and preserving cardiac output at the expense of some cyanosis.

OTHER INTERVENTIONS

Shunt creation — Percutaneous creation of an atrial level shunt (atrial septostomy) is occasionally performed in patients with PH-CHD when a shunt is not present; this strategy is based on data that survival is improved in patients with PH and persistent shunts compared with those without shunting [26].

This approach is generally reserved for patients with progressive right heart failure despite appropriate PH therapies. A revised technique for safe creation of a reverse Potts shunt (connection between the left pulmonary artery and the descending thoracic aorta to allow offloading of the right ventricle in patients with PAH with suprasystemic pulmonary artery pressures) has been developed [27]. This technique utilizes a radiofrequency wire to create a controlled connection followed by covered stent placement and serial balloon dilation of the stent to create the shunt. This procedure resulted in substantial durable clinical improvement in three patients that were failing maximal medical therapy.

Intervention for obstructive lesions — Another potentially reversible cause of PH-CHD is a left heart obstructive lesion (eg, mitral stenosis), which should be treated according to standard recommendations. (See "Surgical and investigational approaches to management of mitral stenosis".)

TRANSPLANTATION — Heart and lung transplantation or lung transplantation with congenital defect repair or mechanical circulatory support are alternative advanced therapeutic strategies for selected adults with severe PH with CHD and refractory right heart failure despite medical therapy [28]. Patients with CHD who may require lung or heart-lung transplantation should be evaluated and managed in tertiary care centers with medical and surgical personnel with experience and expertise in the management of congenital heart disease and lung or heart-lung transplantation [29].

Transplantation should be reserved for severely symptomatic patients, since overall survival with medical management is usually quite good even in patients with severe pulmonary arterial disease [30]. For example, in one report of 37 patients with Eisenmenger syndrome and severe pulmonary arterial hypertension (PAH) managed without transplantation, the one- and three-year survival rates were 97 and 77 percent, respectively [31]. Selection of candidates for lung transplantation and heart-lung transplantation is discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Lung transplantation' and "Lung transplantation: General guidelines for recipient selection" and "Heart transplantation in adults: Indications and contraindications".)

Outcomes are also reasonably good in patients with PAH-CHD who undergo transplantation [32,33]. Short- and long-term survival rates following heart-lung transplantation are similar to the survival noted for other forms of PH. The largest transplantation experience comes from a review of 605 Eisenmenger patients in the United Network for Organ Sharing/International Society for Heart and Lung Transplantation joint thoracic registry [32]. The following findings were noted:

●Eisenmenger syndrome was associated with atrial septal defect in 171, ventricular septal defect in 164, multiple congenital anomalies in 68, and patent ductus arteriosus in 32. The most common procedure was heart-lung transplantation (430 patients) compared with 106 bilateral and 69 single lung transplants.

●Patient survival was greater with heart-lung transplantation compared with isolated lung transplantation (81 versus 68 percent at 30 days and 70 versus 55 percent at one year). The benefit of heart-lung transplantation was greatest in patients with a ventricular septal defect as the cause of Eisenmenger syndrome, while the outcomes were worst in patients with an atrial septal defect.

Longer-term follow-up was provided in a series of 51 patients with Eisenmenger syndrome who underwent heart-lung transplantation [33]. Eight patients (16 percent) died early and the 1-, 5-, and 10-year survival rates were 73, 51, and 28 percent, respectively. These outcomes were the same as those in patients undergoing heart-lung transplantation for other indications.

The choice of transplant procedure is based upon numerous factors. Cardiac repair with bilateral lung transplantation generally has a more manageable postoperative course and greater functional reserve than single lung transplantation. On the other hand, isolated lung transplantation enables greater use of the limited supply of donor organs, generally requires shorter time on cardiopulmonary bypass, and may allow late reversal of arteriopathy in the remaining native lung. For patients with unsuccessfully repaired or uncorrectable lesions, and/or severely depressed left ventricular function, heart-lung transplantation is the preferred procedure. (See "Lung transplantation: General guidelines for recipient selection" and "Heart-lung transplantation in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in adults" and "Society guideline links: Congenital heart disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Role of disease-specific therapy – Disease-specific therapy includes primary therapy directed at the underlying cause of pulmonary hypertension (PH) and therapy directed at the pathophysiologic process (eg, pulmonary arterial hypertension [PAH]-specific therapy). Disease-specific therapy differs among the various causes and groups of PH (table 1) and is administered along with general management of pulmonary hypertension-congenital heart disease (PH-CHD). (See 'Overview' above and "Pulmonary hypertension in adults with congenital heart disease: General management and prognosis".)

●Patient selection for PAH-specific therapy – Hemodynamic cardiac catheterization is required to identify patients with PH-CHD who are candidates for PAH-specific therapy as noninvasive evaluation of PH has not been standardized for patients with CHD. (See 'Patient selection' above and "Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis", section on 'Confirmation of diagnosis'.)

●Agent selection for PAH-specific therapy – The approach to PAH-specific therapy for patients with PAH-CHD is generally similar to that for group 1 PAH.

A key exception is that calcium channel blocker therapy is usually not used in patients with PAH-CHD. However, patients with PAH with small or closed congenital shunts may be candidates for acute vasodilator testing as a guide to calcium channel blocker therapy, as they may respond similarly to patients with idiopathic PAH.

For patients with PAH-CHD with shunts, avoidance of central lines is of particular concern given the risks of paradoxical emboli and infectious complications. Accordingly, when parenteral therapy is indicated, subcutaneous treprostinil may be used to avoid use of an indwelling line. (See 'Agent selection' above and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Baseline risk assessment'.)

●Role of intervention – The role of interventional treatments for the patient with PH-CHD depends on the underlying lesion, pathophysiology, and degree of pulmonary vascular disease. Reversible causes of PH should be evaluated and corrected. A decision of whether or not to close a defect is based upon factors including the direction of flow, pulmonary vascular resistance (PVR), and the type of defect. (See 'Shunt closure' above.)

●Transplantation – Heart and lung transplantation or lung transplantation with repair of congenital defect are treatment options for selected severely symptomatic patients with Eisenmenger syndrome. (See 'Transplantation' above.)