Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis

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 'Epidemiology' below.)

The clinical manifestations and diagnosis of PH-CHD are discussed here. Management of PH-CHD and the evaluation, prognosis, and management of Eisenmenger syndrome are discussed separately. (See "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].

●Pulmonary hypertension-congenital heart disease (PH-CHD) – Patients with PH-CHD have a variety of types of PH (table 1). PH-CHD is thus an overarching term of PH in patients with CHD. In these patients, PH is commonly, but not always, caused by CHD. The most common type of PH-CHD is congenital shunt-related pulmonary arterial hypertension (PAH). Given the epidemic of heart failure (from systemic ventricular dysfunction) in patients with CHD, the prevalence of type 2 PH is likely rising among patients with CHD (see 'Classification' below and 'Pathogenesis' below). However, with rapidly increasing numbers of CHD patients with heart failure from systemic ventricular dysfunction, pulmonary venous PH (group 2) and mixed forms are increasing.

●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), particularly PH from left heart disease. 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 [4]. 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 [5]. PAH associated with 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 irreversible PAH and is characterized by the triad of large intra- or extracardiac congenital 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) [6,7]. The pulmonary arterial disease in Eisenmenger syndrome is caused by increased pulmonary blood flow and/or elevated PAP.

CLASSIFICATION

Groups — The population of patients with PH-CHD is heterogeneous, predominantly in group 1, although some are in other groups of PH (table 1 and table 3) [3]. In most patients with PH-CHD, the PH is caused by CHD, but in some cases the PH is unrelated to the CHD.

●Group 1 – Most patients with PH-CHD have group 1 PH (precapillary or pulmonary arterial hypertension [PAH]). PAH associated with CHD can be classified into the following subgroups, as described in the 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines for PH [4]:

•Eisenmenger syndrome – Eisenmenger syndrome is the most severe end-stage form of congenital shunt-related PAH, when irreversible pulmonary vascular disease is manifest. The disorder is characterized by the triad of large intra- or extracardiac defect with an initial net systemic-to-pulmonary shunt (ventricular, atrial, or great artery (table 2)), PAH with shunt reversal (net right-to-left) or bidirectional shunting, and resulting hypoxemia with cyanosis (figure 1A-B) [6,7]. The pulmonary arterial disease in Eisenmenger syndrome is caused by increased pulmonary blood flow; therefore, diagnosis of Eisenmenger syndrome requires exclusion of other causes of PH.

•PAH associated with ongoing systemic-to-pulmonary shunt – In this subgroup, defects are moderate to large, pulmonary vascular resistance (PVR) is mildly to moderately increased, and there is systemic-to-pulmonary shunting with no cyanosis at rest.

•PAH with small/coincidental defect – In this subgroup, PVR is markedly elevated in the presence of cardiac defects considered hemodynamically insignificant (for adults, this generally applies to ventricular septal defects [VSD] <1 cm and atrial septal defects <2 cm), which do not account for the development of PAH. The clinical presentation is similar to that of idiopathic PAH, and PAH is likely not caused by CHD.

•PAH after defect correction – This subgroup includes patients with persistent PAH immediately after defect correction as well as patients with PAH that recurs or develops months or years after defect correction in the absence of a hemodynamically significant postoperative lesion. Some patients in the subgroup may have PAH not caused by CHD.

●Group 2 – There is an increasing number of patients with PH-CHD with group 2 PH (caused by disease of the systemic ventricle and its valves). Causes include left heart inflow or outflow obstruction, mitral valve disease (or, in systemic right ventricles, tricuspid valve disease), or left heart systolic and/or diastolic dysfunction with resultant pulmonary venous hypertension.

While some patients with group 2 PH have only postcapillary PH, some patients with group 2 PH have disproportionately high pulmonary artery pressure due to elevated PVR reflecting the effects of their CHD (eg, late repair of a VSD) on the pulmonary arterial vasculature, 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. (See "Pulmonary hypertension in adults with congenital heart disease: General management and prognosis".)

●Group 3 – Group 3 PH is caused by lung disease and/or hypoxia. Some patients with PH-CHD have group 3 PH due to concomitant lung diseases (including acquired diseases such as sleep apnea, chronic obstructive pulmonary disease, or interstitial lung disease) or kyphoscoliosis. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults".)

●Group 4 – Some patients with PH-CHD have group 4 PH which is caused by pulmonary artery obstructions such as chronic pulmonary thromboembolic disease. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension".)

●Group 5 – Some patients with PH-CHD have group 5 PH (caused by unclear or multifactorial mechanisms) such as extrinsic compression of the pulmonary arteries or vasculitis (table 3). (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)

Some patients with PH-CHD in group 5 have PH secondary to increased flow through the pulmonary vasculature without elevated PVR; 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 (table 3).

EPIDEMIOLOGY — 

PH-CHD has been estimated as occurring in 3 to 10 percent of individuals with CHD [1,2]. PH-CHD is more common in patients with shunt lesions, females, and older CHD patients, and is associated with excess mortality and higher health care costs [1] (see "Pulmonary hypertension in adults with congenital heart disease: General management and prognosis"). Among populations of patients with congenital systemic-to-pulmonary shunts, the prevalence of PH varies from <5 percent to >15 percent, with the higher rates observed among older individuals [1,2,8,9]. Early diagnosis and repair of CHD has decreased the percentage of patients with CHD who develop severe pulmonary arterial hypertension with Eisenmenger syndrome; however, the overall number of patients with PH-CHD is increasing because more patients with complex and palliated CHD survive to adulthood, and there is a rapidly increasing number of patients with CHD and systemic ventricular dysfunction with group 2 PH [10].

PATHOGENESIS

Spectrum of causes — In patients with PH-CHD, PH is usually, but not always, caused by CHD. In PH-CHD, the PH can be purely precapillary (elevated pulmonary vascular resistance [PVR] with normal pulmonary venous pressure, as for those in groups 1, 3, and 4, and for some in group 5), purely postcapillary (secondary to elevated pulmonary venous pressure with normal PVR, as for some with group 2 PH), or a combination of the two (mixed PH, as for others with group 2 PH). Patients in group 5 may have isolated precapillary PH, isolated postcapillary PH or both.

Pathophysiology of shunt-related PH-CHD

Causes — As noted above, PH-CHD with group 1 pulmonary arterial hypertension (PAH) can be caused by ventricular, atrial, or aortic shunts (table 2), especially when they are large and hemodynamically nonrestrictive, due to increased pulmonary blood volume and/or pressure overload. Other disorders, including complex anatomic abnormalities, can also be associated with PAH and Eisenmenger syndrome. A communication between the systemic and pulmonary circulations is present, generally with an associated initial net left-to-right shunt.

In study of 201 children and adults with Eisenmenger syndrome followed from 1976 to 1992, the most common defects were ventricular septal defects (VSD; 33 percent), atrial septal defects (ASD; 30 percent), and patent ductus arteriosus (PDA; 14 percent) [11]. The type of lesions and the number of patients with shunt-related PAH is largely dependent on access to medical care. As outlined above, in resource-abundant countries, where timely repair of shunt lesions is available, incidence and prevalence of patients with Eisenmenger syndrome is decreasing.

In patients with CHD, the normal anatomic relations between the atria, ventricles, and great vessels may be altered. For simplicity, in the discussions that follow, the term "right ventricle" will be used to describe the ventricle from which the main pulmonary artery arises; the term "left ventricle" will be used to describe the ventricle from which the aorta arises.

●In utero – Systemic-to-pulmonary communications usually do not have major effects on fetal blood flow pathways. Right-to-left shunting at the atrial level (across the foramen ovale) and across the PDA is normal in utero, and the high PVR of the fetus limits left-to-right shunting.

●After birth – In the postnatal period, there is normally a rapid decline in PVR and an increase in right ventricular compliance, resulting in a net left-to-right shunt and an increase in pulmonary blood flow.

In most patients with systemic-to-pulmonary communications, some shunting occurs in both directions. This is expected since there is fluctuation in the pressure gradients between systemic and pulmonary circulations during the cardiac cycle due to changes in intrathoracic pressure associated with respiration, and changes in venous return associated with exercise, positional changes, and other factors. The convention of referring to a shunt as "left-to-right" or "right-to-left" is therefore typically an expression of the net result of bidirectional shunting.

The extent of shunt flow is assessed as the ratio of measured pulmonary blood flow (Qp) to systemic blood flow (Qs). In the normal case, where no connection exists, the ratio Qp:Qs is 1:1. Net left-to-right shunting results in a Qp:Qs >1, while net right-to-left shunting results in a Qp:Qs <1. For example, a Qp:Qs of 2:1 indicates that the pulmonary blood flow is twice that of systemic blood flow. (See "Pathophysiology of left-to-right shunts".)

The increase in pulmonary blood flow with net left-to-right shunting eventually may lead to pulmonary vascular disease (picture 1) and increased PVR. The increase in PVR results in a rise in pulmonary artery pressure (PAP) which is called "pulmonary artery hypertension" or "pulmonary arteriolar hypertension" (PAH) to emphasize the etiologic influence of disease in the pulmonary arterioles. As PAH worsens, the shunt may reverse with net right-to-left shunting (figure 1A-B) [12,13]. With shunt reversal, systemic venous blood returning to the right side of the heart passes through the communication, reducing the oxygen saturation of the systemic arterial blood in the left heart and causing cyanosis.

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 [14].

●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) [15]. Endothelin levels decrease after successful repair of the shunt [16].

●Plasma thromboxane B2 levels are also elevated in patients with PAH due to CHD [17]. Thromboxane B2 causes platelet activation and constriction of pulmonary arterioles.

Shunt size and defect type — The risk of developing Eisenmenger syndrome (ie, irreversible pulmonary vascular disease with shunt reversal) appears to be determined by the size of the initial left-to-right shunt and the volume of pulmonary blood flow. Vascular injury is related to the degree and duration of volume overload alone with a pretricuspid shunt, whereas high-pressure shear forces also contribute to pulmonary vascular disease in posttricuspid shunt lesions. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (group 1)".)

Patients with Eisenmenger syndrome due to posttricuspid shunt lesions always experience PH from birth. This is not the case in patients with pretricuspid shunt lesions. This explains the differences in right ventricular remodeling that translates into better prognosis in patients with Eisenmenger syndrome from posttricuspid shunt lesions [18,19].

●Posttricuspid shunts – These include VSDs, PDA, truncus arteriosus, and aorto-pulmonary window. These larger shunts are associated with increased risk of Eisenmenger syndrome, with elevated pulmonary artery pressure transmitted to the pulmonary vasculature.

In patients with a large (nonrestrictive) posttricuspid 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 PVR 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 1B) (ie, Eisenmenger syndrome) [6,7].

Some patients with Eisenmenger syndrome in the setting of a posttricuspid shunt lesion may never manifest a large net left-to-right shunt [20,21]. These are patients with large posttricuspid shunt lesions and unobstructed pulmonary artery flow, associated with persistent systemic pulmonary artery pressures after birth. Usually, with postpartum decrease of PVR, left-to-right shunting occurs, typically leading to clinical left heart failure. In some of these patients, PVR may, however, not decrease after birth, preventing significant left-to-right shunting. If not recognized and diagnosed in a timely manner, elevated pulmonary blood pressures will lead to pulmonary vascular disease, eventually irreversible, as outlined above. Progressive increase in PVR will eventually lead to progressive right-to-left-shunting with cyanosis.

●Pretricuspid shunts – These include ASDs and partial anomalous pulmonary venous return. These shunts initially cause no additional pressure load to the pulmonary vasculature. Only approximately 10 percent of patients with unrepaired atrial septal defects develop PAH and Eisenmenger syndrome, compared with 50 percent of patients with unrepaired VSD and nearly all patients with unrepaired truncus arteriosus [22].

In patients with pretricuspid 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 underperfused vessels. Thus, a rise in PAP occurs only in a subset of patients, and an increased PVR does usually not manifest until adult life [6,7]. (See "Clinical manifestations and diagnosis of atrial septal defects in adults" and "Isolated atrial septal defects (ASDs) in children: Classification, clinical features, and diagnosis".)

CLINICAL MANIFESTATIONS — 

The clinical presentation of adult patients with PH-CHD varies, depending upon the underlying defect, the degree and direction of shunting, and the severity of PH.

Symptoms and signs — Patients with PH-CHD may be asymptomatic or present with exertional dyspnea, fatigue, decline in exercise capacity or functional status, abdominal bloating and discomfort, exertional syncope, or angina. While, in patients with PH-CHD in group 2, symptoms of heart failure dominate, patients with shunt lesions in group 1 may experience specific symptoms and signs that are the focus of the following discussion.

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. (See "Pulmonary hypertension in adults with congenital heart disease: General management and prognosis".)

Physical examination findings in the patient with PH-CHD are similar to those in patients with other causes of PH. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations'.)

Early physical signs include:

●In patients with no shunt or with a shunt distal to the tricuspid valve, the jugular venous pulse is usually normal. In other cases, a prominent A wave is seen due to right atrial contraction, which generates a high pressure in order to fill the hypertrophied right ventricle (figure 3). (See "Assessment of the jugular venous pressure".)

●There is generally a loud P2. A right ventricular impulse and a palpable pulmonary closure sound (P2) are commonly found on precordial palpation.

●There is usually no murmur, but an ejection sound is common due to dilation of the pulmonary artery. (See "Auscultation of cardiac murmurs in adults" and "Auscultation of heart sounds".)

With progressive right heart failure, the following changes become apparent:

●The mean jugular venous pressure increases, as does the magnitude of the A wave. With the development of tricuspid regurgitation, the V wave also increases. (See "Assessment of the jugular venous pressure".)

●The increase in venous pressure and/or neurohormonal activation can lead to peripheral edema, hepatomegaly, and ascites [23,24]. (See "Right heart failure: Clinical manifestations and diagnosis", section on 'Symptoms and signs'.)

●Murmurs of tricuspid and pulmonic regurgitation become audible and occasionally palpable. Tricuspid regurgitation in this setting is secondary to dilation of the tricuspid annulus and right ventricle, and is not a sign of primary valve disease [25]. (See "Auscultation of cardiac murmurs in adults" and "Tricuspid regurgitation: Etiology, clinical features, and evaluation".)

In patients with PH-CHD with shunt lesions, reversal of the shunt may lead to progressive cyanosis. In earlier stages of irreversible pulmonary vascular disease, patients may experience desaturation or cyanosis with exercise only.

Physical examination of the patient with manifested Eisenmenger syndrome demonstrates central cyanosis and digital clubbing (figure 4 and picture 2). Most affected patients have diffuse central cyanosis, and clubbing involves all extremities equally. However, the pattern and degree of cyanosis and clubbing depends upon the patient's hemodynamic status and cardiovascular anatomy. An often mentioned example is the patient with a patent ductus arteriosus and Eisenmenger syndrome, in whom the right-to-left shunt through the ductus typically delivers unoxygenated blood distal to the left subclavian artery. This results in differential cyanosis and clubbing that only involves the lower extremities.

Clinical deterioration may occur during general anesthesia, pregnancy, 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 "Pulmonary hypertension in adults with congenital heart disease: General management and prognosis", section on 'Conditions and procedures to avoid'.)

Initial test findings — Initial test findings in patients with PH-CHD (with a focus on patients with shunt lesions and Eisenmenger syndrome) are described here. Further testing for diagnosis and evaluation are discussed below. (See 'Confirmation of diagnosis' below.)

Laboratory tests — Patients with cyanosis have secondary erythrocytosis; hemoglobin and hematocrit levels should be interpreted accordingly. Iron deficiency is common in cyanotic patients and may be detected by reduced serum ferritin or abnormal iron and iron binding measurements. Of note, some 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 [26]. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia", section on 'Hypoxia/cardiopulmonary disease' and "Diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)

Electrocardiogram — An electrocardiogram (ECG) 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 ECG usually reveals abnormal findings in patients with PH-CHD. These include evidence of right atrial abnormality (tall, narrow P wave) (waveform 1 and waveform 2), right axis deviation, and right ventricular hypertrophy or biventricular hypertrophy with associated ST-T wave changes (waveform 3). (See "ECG tutorial: Chamber enlargement and 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 dilated central pulmonary arteries; peripheral pulmonary artery pruning (abrupt attenuation and/or termination of peripheral pulmonary artery branches); neovascularity, which is better seen on computed tomography (CT) scan [27]; right heart enlargement; and right ventricular hypertrophy (image 1). The right atrium is prominent and the left heart border becomes straight or convex due to the 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.

DIAGNOSIS AND EVALUATION

When to suspect PH-CHD — 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.

In patients with shunt-related PH, the diagnosis may not be established until adulthood and the development of symptoms or overt features of PH such as syncope, atrial and ventricular arrhythmias, cyanosis, and late complications of right and left heart failure.

Initial evaluation

Initial approach — A comprehensive workup for diagnosis and evaluation is recommended for all patients with suspected PH-CHD. The initial evaluation of patients with suspected PH-CHD should include the following elements [28]:

●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.)

●ECG. (See 'Electrocardiogram' above.)

●Echocardiography to determine if PAP is elevated and to assess cardiac anatomy and function. The assessment of PAP 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. Echocardiography also allows comprehensive assessment of systemic ventricular function and thus may suggest group 2 PH-CHD. (See 'Echocardiography' below.)

●CT or cardiovascular magnetic resonance (CMR) imaging is performed if echocardiography is suboptimal for assessment of cardiac structure and function. CMR also allows accurate assessment of pulmonary and systemic blood flows and may be helpful for confirmation of PVR in patients with shunt lesions and borderline PVR measurements by cardiac catheterization.

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:

●Right heart findings – These include increased right ventricular wall thickness (right ventricular hypertrophy) and right atrial enlargement. Increased tricuspid regurgitation systolic flow velocity and increased end-diastolic flow velocity of pulmonic regurgitation suggest elevated PAP. The elevation in pressure leads to increased right ventricular wall thickness with paradoxical bulging of the septum into the left ventricle during systole.

In patients with advanced PH-CHD, right heart failure occurs and can result in progressive right ventricular dilation and hypokinesis. The septum shows abnormal diastolic flattening, and right atrial dilation and secondary tricuspid and pulmonic regurgitation are seen (movie 1 and movie 2). 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 [29].

●Identification of shunt – Imaging may demonstrate the underlying cardiac defect responsible for the initial left-to-right shunt (movie 3 and movie 4 and movie 5 and movie 6). However, 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. Agitated saline contrast can be helpful in confirming a suspected intracardiac shunt but should be avoided when a large intracardiac shunt has been established.

However, a patent ductus arteriosus (PDA) can be easily missed using standard echo-Doppler imaging with 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. Sometimes, it may be necessary to measure oxygen saturation in lower extremities after exercise (eg, a six-minute walk test) to identify right-to-left shunting in patients with PAH in the setting of a large PDA.

●Additional features – 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 [4]. In addition, Doppler features suggesting PH include pulmonary acceleration time less than 80 ms and/or systolic notching of the right ventricular outflow tract profile [30]. Pulmonary vascular resistance (PVR) can be estimated by echo-Doppler parameters [31]. Although frequently used, these echo-Doppler parameters have not been validated in CHD patients.

Two-dimensional echocardiography may be limited by poor acoustic windows in patients with pulmonary arterial hypertension (PAH). Transesophageal echocardiography (TEE) should be considered in patients with suspected PH with suboptimal transthoracic images, in an effort to exclude CHD. TEE may be contraindicated in some patients given the potential risk of sedation. Generally, such tests are best performed at specialized centers with expertise in the care of patients with congenital heart disease. A TEE (with agitated saline contrast) may provide additional important anatomic information when the TTE images are not technically sufficient to identify the structural and functional abnormalities [32]. 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.

CT or CMR — If cardiac defects, cardiac anatomy, and right ventricular function cannot be adequately assessed by echocardiography, imaging by cardiac 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. CMR also allows accurate quantification of pulmonary blood flows.

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. CT of the pulmonary arteries can reveal enlargement, thrombosis, and mural calcification of the pulmonary trunk and its proximal branches [33,34]. High-resolution CT imaging with lung windows can also be added to screen for lung pathology. Within the lung parenchyma, embolic infarction, hemorrhage, neovascularity, lobular ground glass opacification, and hilar and intercostal collaterals may also be seen [27]. The last three abnormalities appear to occur more frequently in cyanotic than in acyanotic PAH and may correspond to the histologic findings of malformed, dilated muscular arteries within the alveolar septae and congested capillaries within the walls of both alveoli and medium-sized pulmonary arteries [27]. These lesions are more common and more severe with posttricuspid right-to-left shunts at the level of the ventricles or great arteries.

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 PAH and may be used to assess right ventricular function in settings where there is consideration of lung transplantation.

Compression of a coronary artery has been reported in PH-CHD patients; this may be identified by CT, CMR, or coronary angiography [35].

Confirmation of diagnosis — The diagnosis of PH is generally confirmed by cardiac catheterization with vasoreactivity testing, ideally performed at a specialty center [36]. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Initial diagnostic evaluation (noninvasive testing)' and 'Cardiac catheterization' below.)

Cardiac catheterization — Hemodynamic cardiac catheterization is recommended at least once for all patients with PH-CHD to confirm PH and define underlying pathophysiology [37]. Cardiac catheterization enables characterization of the cardiac shunt and PVR. 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'.)

Multiple factors may confound the hemodynamic evaluation and quantification of PAH in Eisenmenger syndrome, especially in patients with complex CHD. These may include:

●Pulmonary venous hypertension due to left atrial hypertension or atrioventricular valve regurgitation or stenosis.

●Pulmonary venous obstruction.

●Pulmonary parenchymal disease or restrictive lung disease.

●In situ pulmonary artery thrombosis.

●Altered anatomic relations and hemodynamics that may impede routine catheter advancement and positioning.

●PVR is flow dependent, so pulmonary artery pressure may not necessarily fall in proportion to the reduction in shunt and pulmonary blood flow.

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

Cardiac catheterization may also be important in group 2 PH-CHD to determine whether there is pure pulmonary venous PH or an additional PAH component. The latter is important for determining candidacy for transplant. (See "Heart transplantation in adults: Indications and contraindications", section on 'Elevated pulmonary vascular resistance'.)

Tests to evaluate patients with PH-CHD — The following tests are performed to evaluate disease severity in patients with confirmed PH-CHD with shunt lesions:

●Natriuretic peptide levels – In patients with PH-CHD, we suggest monitoring B-type natriuretic peptide (BNP) or N-terminal pro-BNP 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 [38,39].

●Pulse oximetry – In patients with PH-CHD, pulse oximetry is performed at baseline and repeated when there has been a change in clinical status. Some clinics check saturations routinely with intake vital signs.

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.

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.

●Six-minute walk test – A six-minute walk test or similar exercise test may be considered as part of the functional assessment. This also provides information about functional limitation and oxygen desaturation; it is helpful to monitor status in patients with documented PH-CHD and is helpful in evaluating prognosis. A 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.

Tests to exclude other causes of PH — The following tests are generally performed in all patients with PH-CHD to identify alternate or concurrent conditions:

●Nuclear lung scintigraphy is performed to assess for pulmonary thromboembolic disease. Nuclear lung scintigraphy or ventilation/perfusion (V/Q) lung scanning is recommended for all patients with PH-CHD and confirmed PAH/elevated PVR 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 [40]. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension".)

●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. These tests are also generally performed in all PH-CHD patients to exclude concomitant lung disease.

●Pulse oximetry – Overnight oximetry is recommended to assess for nocturnal hypoxemia and sleep-disordered breathing.

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of PH-CHD includes:

●Elevated right ventricular systolic pressures without PH – Elevated tricuspid regurgitation velocity by echo-Doppler identifies elevated right ventricular systolic pressures. Right ventricular systolic pressure may be elevated without PH in the presence of right ventricular outflow tract obstruction such as pulmonary valve obstruction, prosthesis or conduit obstruction, double-chamber right ventricle, or infundibular or peripheral pulmonary artery stenosis. In all patients with elevated tricuspid regurgitation velocity, right ventricular outflow tract obstruction should be excluded.

●Elevated right ventricular systolic pressures due to peripheral pulmonary artery stenosis – This condition can be identified by color, pulsed wave, and continuous wave Doppler, as well as CT, CMR imaging, or cardiac catheterization.

●Erroneous measurement – 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. (See 'Tests to exclude other causes of PH' above.)

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

●Pulmonary hypertension-congenital heart disease – Patients with pulmonary hypertension (PH) and congenital heart disease (CHD) have heterogenous types and causes of PH (table 1). In patients with PH-CHD, PH is commonly but not always caused by CHD. (See 'Definitions' above and 'Classification' above.)

●Eisenmenger syndrome – Eisenmenger syndrome is the most severe end-stage form of congenital shunt-related pulmonary arterial hypertension (PAH) when irreversible pulmonary vascular disease is manifest. The disorder is characterized by the triad of systemic-to-pulmonary shunt (ventricular, atrial, or great artery (table 2)), PAH with shunt reversal (right-to-left), and resulting hypoxemia with cyanosis (figure 1A-B). The pulmonary arterial disease in Eisenmenger syndrome is caused by increased pulmonary blood flow and/or elevated pulmonary artery pressure (PAP). (See 'Definitions' above and 'Classification' above and 'Pathophysiology of shunt-related PH-CHD' above.)

●Epidemiology – Patients with PH-CHD represent a growing population, estimated as affecting 3 to 10 percent of patients with CHD, with higher prevalence rates observed in older patient populations. (See 'Epidemiology' above.)

●Classification – Patients with PH-CHD represent a heterogeneous population, predominantly in group 1 (precapillary or PAH), though some are in other groups (table 1). (See 'Classification' above.)

●Clinical presentation – 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). Specifically, in patients with PH-CHD in the setting of shunt lesions, right-to-left shunting with cyanosis is common.

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

●Diagnostic evaluation – Diagnostic evaluation of PH-CHD includes a history and physical examination, pulse oximetry, laboratory testing, cardiovascular imaging (starting with echocardiography with additional imaging as needed), and confirmation of PH by cardiac catheterization. Tests to identify alternate or concurrent conditions include nuclear lung scintigraphy, pulmonary function tests with diffusion capacity, and overnight oximetry. (See 'Initial evaluation' above and 'Confirmation of diagnosis' above.)The differential diagnosis of PH-CHD includes other causes of elevated right ventricular systolic pressures, spurious diagnosis of PH due to erroneous echo-Doppler measurement, and other causes of PH such as pulmonary thromboembolism. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Thomas P Graham, Jr, MD, for his contributions as a Section Editor to previous versions of this topic review.