INTRODUCTION — Approximately 3 to 10 percent of patients with congenital heart disease (CHD) develop pulmonary arterial hypertension (henceforth described as pulmonary hypertension-congenital heart disease [PH-CHD]) [1,2]. Early diagnosis and repair of CHD has decreased the number of patients with Eisenmenger syndrome; however, the overall number of PH-CHD patients is increasing because more patients with complex and palliated CHD survive to adulthood [3]. PH-CHD is more common in women, patients with shunt lesions, and older CHD patients, and is associated with excess mortality and increase in health care costs [1].

The clinical manifestations and diagnosis of PH-CHD in adults are discussed here. Management of PH-CHD and the evaluation, prognosis, and management of Eisenmenger syndrome are discussed separately. (See "Management and prognosis of pulmonary hypertension in adults with congenital heart disease" and "Evaluation and prognosis of Eisenmenger syndrome" and "Management of Eisenmenger syndrome".)

DEFINITION — Pulmonary hypertension (PH) is defined as a mean pulmonary artery pressure >20 mmHg at rest. PH can be purely postcapillary (secondary to elevated pulmonary venous pressure with normal pulmonary vascular resistance [PVR]), purely precapillary (elevated PVR with normal pulmonary venous pressure), or a combination of the two (mixed PH). PH-congenital heart disease (PH-CHD) can also be secondary to increased flow through the pulmonary vasculature; this type of PH is not typically observed in non-CHD populations, aside from high output states such as severe anemia, thyrotoxicosis, cirrhosis, and large dialysis fistulae.

CLASSIFICATION — Patients with pulmonary hypertension-congenital heart disease (PH-CHD) represent a heterogeneous patient population, predominantly in group 1 (precapillary or pulmonary arterial hypertension [PAH]) PH clinical classification [4] (table 1). (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Diagnosis'.)

In the past, a classification system based on cause of PH-CHD was used and patients were classified into the following groups:

●PH associated with systemic-to-pulmonary shunt. This group includes a subgroup of patients with Eisenmenger syndrome (the triad of systemic-to-pulmonary cardiovascular communication, pulmonary arterial disease, and cyanosis). (See "Evaluation and prognosis of Eisenmenger syndrome".)

●PH with small/coincidental defects.

●PH after defect correction. In some patients with congenital heart disease, PH develops years after shunt closure.

While PH-CHD is predominantly group 1 PH (PAH), some patients with PH-CHD have left heart inflow or outflow obstruction, mitral valve disease, or left heart systolic and/or diastolic dysfunction with resultant pulmonary venous hypertension (group 2, PH owing to left heart disease). Some of these patients may have disproportionately high pulmonary artery pressure and resistance reflecting consequences of their CHD on the pulmonary arterial vasculature (eg, late repair of a ventricular septal defect), combined with elevated left heart filling pressures (eg, restrictive left ventricular filling). This mixed pre- and postcapillary PH is complex to manage, requiring attention to both the pre- and postcapillary components. PH-CHD may also occur in the setting of concomitant lung diseases (including acquired diseases such as sleep apnea, chronic obstructive pulmonary disease, or interstitial lung disease) or kyphoscoliosis (group 3, PH owing to lung disease and/or hypoxia), pulmonary thromboembolic disease (group 4, chronic thromboembolic PH), and from other more uncommon causes such as extrinsic compression of the pulmonary arteries or vasculitis (group 5, PH with unclear multifactorial mechanisms).

PATHOGENESIS — Pulmonary arterial hypertension (PAH) may develop in patients with congenital heart disease (CHD) with left to right intracardiac or extracardiac shunts (atrial, ventricular, and great artery defects), especially when they are large and hemodynamically nonrestrictive, due to increased pulmonary blood volume and/or pressure overload. Increases in flow through the pulmonary vasculature cause shear forces that disrupt the vascular endothelium and activate cellular mechanisms critical to the pathogenesis and progression of PAH [5].

Eisenmenger syndrome is the most severe end-stage form of shunt-related PAH; the disorder is characterized by severe PAH with shunt reversal (right-to-left) and resulting hypoxemia (figure 1) [6,7]. Patients with PAH associated with coincidental or small cardiac shunt defects and those with persistent or worsening PAH despite closure of the defect should not be classified as Eisenmenger syndrome, but rather the broader category of PAH-CHD. (See "Pathophysiology of left-to-right shunts", section on 'Pulmonary hypertension' and "Evaluation and prognosis of Eisenmenger syndrome" and "Clinical manifestations and diagnosis of ventricular septal defect in adults".)

The pathogenetic mechanism of damage to the pulmonary vasculature differs in patients with atrial septal defects (ASD) compared with ventricular septal defects (VSD) or patent ductus arteriosus (PDA). Vascular injury is related to the degree and duration of volume overload alone with an ASD, whereas high pressure shear forces also contribute with a VSD and PDA. (See "Isolated atrial septal defects (ASDs) in children: Classification, clinical features, and diagnosis" and "Isolated ventricular septal defects in infants and children: Anatomy, clinical features, and diagnosis" and "Clinical manifestations and diagnosis of ventricular septal defect in adults".)

●In patients with an ASD (pre-tricuspid defects), left-to-right shunting across the defect starts at birth and increases during the neonatal period with maturation of the pulmonary vasculature. The normal pulmonary vasculature is able to accommodate the increased volume of flow by vasodilating and recruiting previously under perfused vessels; thus, pulmonary artery pressures (PAP) do not rise significantly in most patients with an ASD until adult life [6,7].

●In patients with a large (nonrestrictive) VSD or PDA (post-tricuspid defects), severe PH is present from birth because of the large, hemodynamically nonrestrictive defect. Early on, the hemodynamics are characterized by systemic level PAP (severe PH) with a large left-to-right shunt. The combined effect of volume overload and shear forces elevates the pulmonary vascular resistance and reduces the magnitude of the left-to-right shunt (see "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'General physiologic mechanisms'). Eventually, patients develop severe PAH with shunt reversal (right-to-left flow) and resulting hypoxemia (figure 1) (ie, Eisenmenger syndrome) [6,7].

Injured endothelial cells release factors that are known to contribute to PAH:

●Plasma levels of endothelin, a vasoconstrictor and stimulant of vascular smooth muscle cell proliferation, are elevated in patients with PAH due to CHD (figure 2) [8]. Endothelin levels decrease after successful repair of the shunt [9].

●Plasma thromboxane B2 levels are also elevated in patients with PAH due to CHD [10]. Thromboxane B2 causes platelet activation and constriction of pulmonary arterioles.

CLINICAL MANIFESTATIONS — The clinical presentation of adult patients with pulmonary hypertension-congenital heart disease (PH-CHD) varies, depending upon the underlying defect, the degree and direction of shunting, and the severity of PH.

Symptoms and signs — PH-CHD patients may be asymptomatic or present with exertional dyspnea, fatigue, decline in exercise capacity or functional status, abdominal bloating and discomfort, exertional syncope, or angina. Other symptoms and signs related to complications include hemoptysis (which may be caused by intrapulmonary thrombosis or pulmonary hemorrhage) and symptoms and signs caused by cerebral hemorrhage (such as headache, vomiting, and neurologic signs). Fever and other manifestations of infection are seen with infective endocarditis, pneumonia, or intracerebral abscess. Arrhythmias may or may not produce symptoms. Syncope in a patient with PH-CHD with group 1 PH (pulmonary arterial hypertension) is worrisome and should prompt urgent evaluation and aggressive therapy.

Physical examination findings in the patient with PH-CHD are similar to those in patients with other causes of PH, including a right ventricular or parasternal lift on precordial palpation and loud P2 on auscultation. The other findings will depend on the underlying disease and severity of PH. In the setting of advanced disease, features of right heart failure may be present. Patients with PH-CHD with reversal of the shunt may demonstrate mild or moderate cyanosis. Some patients may experience desaturation or cyanosis with exercise. Most patients with Eisenmenger syndrome have central cyanosis and clubbing involving all extremities equally; however, the pattern and degree of cyanosis and clubbing depend upon the patient’s hemodynamic status and cardiac anatomy. Clinical deterioration may occur during general anesthesia, lung infections, development of arrhythmias, and when ascending to altitude. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations' and "Evaluation and prognosis of Eisenmenger syndrome" and "Evaluation and prognosis of Eisenmenger syndrome", section on 'General features'.)

Initial test findings — Initial test findings in patients with PH-CHD are described here. Further testing for diagnosis and evaluation are discussed below. (See 'Key diagnostic tests' below and 'Tests to evaluate patients with PH-CHD' below.)

Laboratory tests — Patients with cyanosis may have a secondary erythrocytosis; hemoglobin and hematocrit levels should be interpreted accordingly. Iron deficiency is common in patients with PH-CHD and may be detected by reduced serum ferritin or abnormal iron and iron binding measurements. Of note, many patients with cyanosis and iron deficiency lack microcytosis and hypochromia; some have macrocytosis and/or hyperchromia, which may be related to coexistent folate or vitamin B12 deficiency [11]. (See "Diagnostic approach to the patient with polycythemia", section on 'Hypoxia/cardiopulmonary disease' and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)

Electrocardiogram — An electrocardiogram is not required for the diagnosis of PH-CHD but is generally obtained as part of the evaluation to provide a baseline for future comparison and to determine rhythm. The electrocardiogram usually reveals abnormal findings in patients with PH-CHD. These include evidence of right atrial enlargement, right axis deviation, and right ventricular hypertrophy or bi-ventricular hypertrophy.

Chest radiograph — A chest radiograph is not required for the diagnosis of PH-CHD but is generally obtained as part of the evaluation to assess lung disease, which may be a concurrent or alternate cause of PH. Typical chest radiograph findings in patients with PH include right heart enlargement, enlarged central pulmonary arteries, and reduced pulmonary vascularity. The right atrium is prominent and the left heart border becomes straight or convex due to dilated and displaced right ventricular outflow tract. Calcification of the pulmonary arteries can occur late in the course of disease. The chest radiograph may occasionally be normal in patients with less severe PH-CHD. Some patients may have lung disease concurrent with or instead of PH-CHD and features of such disease may be identified on the chest radiograph. (See "Evaluation and prognosis of Eisenmenger syndrome", section on 'Evaluation for congenital heart disease related pulmonary arterial hypertension'.)

DIAGNOSIS AND EVALUATION

When to suspect pulmonary hypertension-congenital heart disease — Pulmonary hypertension-congenital heart disease (PH-CHD) should be suspected in CHD patients with persistent cardiac shunt and associated cyanosis, decline in functional status, syncope, lower extremity edema, abdominal distention, or hemoptysis. PH-CHD often first comes to attention when estimated pulmonary artery pressures (PAP) are found to be elevated on echocardiographic assessment.

Approach to diagnosis and evaluation — A comprehensive workup for diagnosis and evaluation is recommended for all patients with suspected PH-CHD. The evaluation of patients with suspected PH-CHD should include the following elements [12]:

●Initial evaluation, including:

•A thorough history and physical examination. (See 'Symptoms and signs' above.)

•Laboratory testing, including a complete blood count (to assess for secondary erythrocytosis). Other suggested tests include serum chemistries (including electrolytes; urea, creatinine, uric acid, and liver function tests; serum ferritin; antinuclear antibody; and other connective tissue disease-related antibody testing if superimposed rheumatologic disease is suspected), human immunodeficiency virus testing, and thyroid function tests to identify associated or contributing conditions. (See 'Laboratory tests' above.)

•Chest radiograph. (See 'Chest radiograph' above.)

•Electrocardiogram. (See 'Electrocardiogram' above.)

●Testing to diagnose PH-CHD and exclude alternate or concurrent conditions:

•Echocardiography to determine if PAP are elevated and to assess cardiac anatomy and function. The assessment of pulmonary artery pressures may not be possible by echocardiography, and there should be a low threshold to perform cardiac catheterization in patients with complex congenital cardiac disease who present with worsening symptoms. (See 'Echocardiography' below.)

•Computed tomography (CT) or cardiovascular magnetic resonance (CMR) as needed to evaluate cardiac anatomy and function if not adequately assessed by echocardiography.

•The diagnosis of PH is generally confirmed by cardiac catheterization with vasoreactivity testing, ideally performed at a specialty center [13]. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Initial diagnostic evaluation (noninvasive testing)'.)

•Nuclear lung scintigraphy to assess for pulmonary thromboembolic disease. (See 'Nuclear lung scintigraphy' below.)

•Pulmonary function tests with diffusion capacity to evaluate pulmonary status. (See 'Pulmonary function tests with volumes and diffusion capacity' below.)

●Additional tests commonly performed for evaluation of patients with PH-CHD:

•Natriuretic peptide levels

•Pulse oximetry

•Six-minute walk

Key diagnostic tests

Echocardiography — Comprehensive two-dimensional and Doppler transthoracic echocardiography (TTE) is generally the initial test that raises the suspicion of PH-CHD. Echocardiography can generally determine the underlying CHD lesion, provide an estimate of PAP using continuous wave Doppler, suggest clues about the pathophysiology of PH, and provide prognostic features.

Echocardiographic findings in PH-CHD include increased right ventricular wall thickness (right ventricular hypertrophy), right atrial enlargement, and increased tricuspid and pulmonary valve regurgitation velocities.

An intracardiac or extracardiac shunt may be present but difficult to visualize by standard two-dimensional echocardiographic imaging due to equalization of pressures between chambers/vessels and bidirectional shunting. Echocardiographic imaging following an agitated saline injection is recommended for all patients with a new diagnosis of PH to exclude an intracardiac/extracardiac shunt such as an occult atrial septal defect (ASD) as a contributing factor. A patent ductus arteriosus (PDA) can be easily missed using standard echo-Doppler and agitated saline injection. Clues to the diagnosis include differential clubbing and cyanosis (cyanosis and clubbing affecting the toes more than the fingers), low velocity bidirectional flow in the region of the PDA, and the appearance of agitated saline in the descending thoracic aorta after peripheral vein injection and appearance in the right heart.

In patients with advanced PH-CHD, right heart failure occurs and can result in right ventricular systolic dysfunction and progressive right heart enlargement with secondary tricuspid and pulmonary valve regurgitation. The presence of a pericardial effusion suggests advanced PH with high right atrial pressure and reduced survival; however, these findings have not been specifically identified as high-risk features in PH-CHD patients [14].

Echo-Doppler features have been described to help determine the etiology of PH in non-CHD patients such as left atrial dilation, and restrictive left heart filling parameters seen in pulmonary venous hypertension. In addition, Doppler features suggesting PH include pulmonary acceleration time less than 80 milliseconds and/or systolic notching of the right ventricular outflow tract profile [15]. PVR can be estimated by echo-Doppler parameters [16]. Although frequently used, these echo-Doppler parameters have not been validated in CHD patients.

A transesophageal echocardiogram may provide additional important anatomic information when the TTE images are not technically sufficient to identify the structural and functional abnormalities [3]. Intracardiac and extracardiac shunts may be very difficult to identify by TTE. Three-dimensional echocardiographic imaging may be helpful in assessment of right heart size and function and also in the assessment of an ASD. Intracardiac echocardiographic imaging is used primarily during interventional procedures.

Cardiovascular magnetic resonance or computed tomography — If cardiac defects, cardiac anatomy and right ventricular function cannot be adequately assessed by echocardiography, imaging by CT or CMR is indicated. Both CT and CMR imaging allow assessment of cardiac anatomy, assessment of pulmonary artery size, and quantification of right ventricular size and function. Occasionally, compression of a coronary artery has been described in a PH-CHD patient; this may be identified by CT, CMR, or coronary angiography [17]. CT is generally preferred over CMR for patients with PH-CHD, since CT angiography may better identify thromboembolic disease and pulmonary artery anomalies than CMR. High-resolution CT imaging with lung windows can also be added to screen for lung pathology. Serial CT and CMR imaging are not routinely performed in PH-CHD patients. Follow-up cross-sectional imaging frequency is individualized and depends on underlying CHD and associated lesions. Serial CMR is being explored as a tool to follow right ventricular function in pulmonary arterial hypertension and may be used to assess right ventricular function in settings where there is consideration of lung transplantation.

Cardiac catheterization — Hemodynamic cardiac catheterization is recommended at least once for all patients with PH-CHD to confirm PH and define underlying pathophysiology [18]. Cardiac catheterization enables characterization of the cardiac shunt and pulmonary vascular resistance (PVR). Once PH is confirmed, vasodilator testing is recommended; this should be done at a center with expertise in catheterization, PH, and management of PH-CHD. For patients with systemic to pulmonary shunts, PVR is an important determinant of correctability. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Right heart catheterization' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Vasoreactive patients'.)

Serial cardiac catheterization may be useful in situations where there is a change in clinical condition and uncertainty has arisen regarding current hemodynamic pattern, severity, and management strategy.

Nuclear lung scintigraphy — Nuclear lung scintigraphy or ventilation/perfusion (V/Q) lung scanning are recommended for all patients with PH-CHD to exclude pulmonary thromboembolic disease. V/Q scintigraphy has a higher sensitivity than CT scan in detecting chronic thromboembolic pulmonary disease as a potential cause of PH [19].

Pulmonary function tests with volumes and diffusion capacity — Lung function tests with assessment of diffusing capacity are recommended during the initial evaluation of all patients with PH to determine whether a pulmonary cause can be identified. This is also generally performed in all PH-CHD patients, unless a clear cause such as a large shunt is identified.

Tests to evaluate patients with PH-CHD — In addition to the above described initial tests, we suggest the following tests to evaluate patients with PH-CHD. (See 'Approach to diagnosis and evaluation' above.)

Natriuretic peptide level — In patients with PH-CHD, we suggest monitoring brain natriuretic peptide or N-terminal of the prohormone of brain natriuretic peptide levels with careful interpretation of results. Extent of elevation of these biomarkers reflects degree of hemodynamic derangement and provides prognostic guidance. However, natriuretic peptide levels do not distinguish between left and right heart failure, may be elevated due to renal dysfunction, and may be spuriously low in severe obesity. The specific evidence for use in PH-CHD remains limited [20,21].

Pulse oximetry — Pulse oximetry at rest and during exercise, with and without administration of supplemental oxygen if desaturation unrelated to cardiac shunt is present, should be performed and may provide information about the response to medical therapy. Overnight oximetry is recommended to assess for nocturnal hypoxemia and sleep-disordered breathing. Finger and toe oximetry are recommended in those with suspected Eisenmenger syndrome. Reduced lower extremity saturation compared with upper extremity saturation should raise the clinical suspicion of a PDA with shunt reversal. Oximetry is repeated during follow-up visits when there has been a change in clinical status. (See "Evaluation and prognosis of Eisenmenger syndrome", section on 'Physical examination' and "Clinical manifestations and diagnosis of patent ductus arteriosus in term infants, children, and adults", section on 'Pulmonary hypertension'.)

Exercise test — Maximal exercise testing is not routinely performed in patients with PH-CHD. However, exercise testing in the form of a six-minute walk test is helpful in revealing functional limitation and oxygen desaturation; it is helpful to monitor status in patients with documented PH-CHD and is helpful in evaluating prognosis. Six-minute walk test is also often used to assess response to medical therapy. Submaximal or maximal cardiopulmonary exercise testing with measures of gas exchange may be useful in some situations in order to further define causes of exercise limitation.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of pulmonary hypertension-congenital heart disease (PH-CHD) includes:

●Right ventricular hypertension in the absence of PH – Elevated tricuspid regurgitation velocity by echo-Doppler identifies right ventricular hypertension but this may be due to right ventricular outflow tract obstruction such as pulmonary valve, prosthesis or conduit obstruction, double chamber right ventricle, infundibular or peripheral pulmonary artery stenosis. These patients can generally be differentiated from PH-CHD by a loud systolic murmur noted on physical examination and identification of the obstruction by echo-Doppler.

●Right ventricular hypertension may be due to peripheral pulmonary artery stenosis, which can be identified by color, pulsed-wave, and continuous-wave Doppler, as well as computerized tomography or magnetic resonance imaging.

●Erroneous measurement of ventricular septal defect velocity instead of tricuspid regurgitation velocity by echo-Doppler may result in a spurious diagnosis of PH. Hemodynamic catheterization may be needed to adequately assess the pulmonary pressures when this is suspected.

●Pulmonary thromboembolism and other secondary causes of PH should be considered and testing performed to exclude these diagnoses.

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".)

SUMMARY AND RECOMMENDATIONS

●Patients with pulmonary hypertension-congenital heart disease (PH-CHD) represent a growing population, affecting 3 to 10 percent of CHD patients. (See 'Introduction' above.)

●Patients with PH-CHD represent a heterogeneous patient population, predominantly in group 1 (precapillary or pulmonary arterial hypertension [PAH]) PH clinical classification, though some are in other groups (table 1). (See 'Classification' above.)

●PH-CHD patients may be asymptomatic or present with symptoms such as exertional dyspnea, fatigue, decline in exercise capacity or functional status, abdominal bloating and discomfort, syncope, hemoptysis, or angina. (See 'Symptoms and signs' above.)

●PH-CHD should be suspected in CHD patients with persistent cardiac shunt and associated cyanosis, decline in functional status, syncope, or hemoptysis. (See 'Diagnosis and evaluation' above.)

●Testing to diagnose PH-CHD and exclude alternate or concurrent conditions includes cardiovascular imaging (starting with echocardiography with additional imaging as needed), confirmation of PH by cardiac catheterization with vasoreactivity testing, nuclear lung scintigraphy and pulmonary function tests with diffusion capacity. (See 'Approach to diagnosis and evaluation' above and 'Key diagnostic tests' above.)

●The differential diagnosis of PH-CHD includes right ventricular (RV) hypertension in the absence of PH, RV hypertension due to peripheral pulmonary artery stenosis, spurious diagnosis of PH due to erroneous echo-Doppler measurement, and secondary causes of PH such as pulmonary thromboembolism.