Approach Considerations
Laboratory studies used in the diagnosis of Eisenmenger syndrome include complete blood cell count, biochemical profiles, and iron studies, in addition to blood gas assessments. Electrocardiography can also reveal signs of an underlying cardiac defect and of right ventricular hypertrophy. Imaging studies can reveal cardiac structural defects and pulmonary changes, including irreversible alterations in the pulmonary system. Histologic findings can be used to determine the stage of pulmonary vascular pathology. The updated 2018 AHA/ACC guidelines for adults with congenital heart disease (ACHD) emphasize the need for advanced cardiac imaging and cardiac catheterization data accuracy to exclude other etiologies of the right-to-left shunt physiology (Class IC recommendation). [29]
Prognostic assessment
Preoperatively, the combination of 100% oxygen or nitric oxide are used to evaluate pulmonary vasculature reactivity in pulmonary hypertension. If the pulmonary vascular resistance (PVR) does not decrease with this test, the PVR is considered irreversible, and the patient may not be a good surgical candidate for corrective cardiac surgery. [30]
Pulmonary angiography can reveal structural alterations in the pulmonary vascular bed. Irreversible changes (consistent with a histologic Heath-Edwards III severity) can be visualized and may include loss of normal arborization of the pulmonary arteries, as well as pulmonary vasculature tortuosity, narrowing, or cut-off.
Laboratory Studies
Complete blood cell count findings include the following:
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Erythrocytosis increases hematocrit and hemoglobin concentration
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Phlebotomy-related iron deficiency decreases the mean corpuscular volume and mean corpuscular hemoglobin concentration
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The red blood cell mass is increased with erythrocytosis
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Bleeding time is prolonged by platelet dysfunction
Biochemical profile findings include the following:
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Increased conjugated bilirubin levels
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Increased uric acid levels
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Urea and creatinine measures are sometimes elevated
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Urinary biochemical analysis reveals proteinuria
Erythrocytic hypoglycemia is an artifactually low blood glucose level caused by increased in vitro glycolysis in the setting of increased red blood cell mass.
Iron study findings include the following:
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Reduced serum ferritin levels due to phlebotomy-related iron store reduction
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Increased total iron binding capacity
Additional findings include the following:
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Pulse oximetry: Cyanosis and decreased saturations may be present
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Arterial blood gas (ABG): Reduced resting partial pressure of carbon dioxide (PaCO 2) due to resting tachypnea, and reduced partial pressure of oxygen (PaO 2) due to right-to-left shunting; mixed respiratory and metabolic acidosis
Chest Radiography and MRI
Radiography
In the early stages of Eisenmenger syndrome, chest radiography reveals a typical appearance of increased pulmonary flow with right ventricular or biventricular enlargement, right atrial or biatrial enlargement, pulmonary vascular plethora, and an enlarged main pulmonary artery. (See the image below.)
Eisenmenger Syndrome. This radiograph reveals an enlarged right heart and pulmonary artery dilatation in a 24-year-old woman with an unrestricted patent ductus arteriosus (PDA) and Eisenmenger syndrome. RA = right atrium.
Advancing pulmonary vascular disease appears as a normal cardiac silhouette with dilated main and branch pulmonary arteries without evidence of pulmonary overcirculation.
In patients with severe pulmonary vascular disease, radiography reveals a normal-sized heart, pruning of the pulmonary vasculature (ie, diminished distal/peripheral pulmonary vascularity), pulmonary infarction, and/or calcification of a patent ductus arteriosus (PDA).
Magnetic resonance imaging
Magnetic resonance imaging (MRI) can be used for the following:
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Estimation of the magnitude of the right-to-left shunt
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Anatomic definition (in some cases)
MRI has advantages over two-dimensional (2-D) echocardiography because it can evaluate the size, systolic function, and muscle mass of the right ventricle. MRI also assesses the main branches of the pulmonary arteries and excludes other cardiac defects that can be missed in echocardiographic evaluation. [32]
Echocardiography
Two-dimensional (2-D) transthoracic imaging can reveal the features of the structural cardiac defect responsible for the shunt. Coexistent structural abnormalities can also be identified. (See the image below.) This modality is the first-line imaging study for the diagnosis of Eisenmenger syndrome.
Eisenmenger Syndrome. Apical, 4-chamber, transthoracic echocardiographic view demonstrating an ostium primum atrial septal defect (ASD) with enlarged right-side chambers. RA = right atrium, RV = right ventricle, LA = left atrium, LV = left ventricle.
Color-flow Doppler interrogation is useful for demonstrating the direction of intracardiac blood flow. (See the following images.) [33]
Eisenmenger Syndrome. This apical, 4-chamber, transthoracic echocardiographic segment shows color Doppler flow across the interatrial septum at the site of a large ostium primum atrial septal defect (ASD). RA = right atrium.
Eisenmenger Syndrome. This is a color Doppler interrogation of the tricuspid valve in a patient with Eisenmenger syndrome. It demonstrates an elevated estimated right ventricular systolic pressure of 106 mm Hg and right atrial pressure, reflecting pulmonary hypertension. TR = tricuspid regurgitation.
Eisenmenger Syndrome. This is a transthoracic Doppler examination of the pulmonic valve in a 24-year-old woman with Eisenmenger syndrome secondary to an uncorrected ostium primum atrial septal defect (ASD). It reveals an elevated estimated pulmonary artery diastolic pressure of 51 mm Hg and right atrial pressure. PR = pulmonic regurgitation.
Pulsed and continuous wave Doppler measurements permit quantification of the intracardiac shunt, right ventricular pressures, and estimation of the pulmonary artery systolic/diastolic and mean pressures with use of the modified Bernoulli equation. [34, 35] Echocardiography can also be used to identify surgical systemic-to-pulmonary shunts. The addition of supine bicycle ergometry can demonstrate increased right-to-left shunting with exercise.
Transthoracic echocardiography has some limitations in evaluating the right ventricle volume given its complex geometry. For this reason, other markers of right systolic ventricular function, such as fractional area shortening, tricuspid annular motion, and systolic tissue Doppler velocities, are used in to describe right ventricular systolic function. [36] Three-dimensional (3-D) echocardiography can be a promising imaging modality to overcome this limitation.
Transesophageal echocardiography
Transesophageal echocardiography is useful for imaging posterior structures, including the atria and pulmonary veins. Note that the hypoxia in these patients makes this test uncomfortable; alternative imaging modalities such as cardiac magnetic resonance should be considered if 2-D echocardiography is inconclusive. (See the image below.)
Eisenmenger Syndrome. This transesophageal echocardiographic image is from the midesophagus of a patient with Eisenmenger syndrome secondary to an unrestricted patent ductus arteriosus (PDA). It shows a severely dilated pulmonary artery (PA). Asc. Ao. = ascending aorta.
Electrocardiography
Electrocardiographic findings are almost always abnormal in Eisenmenger syndrome. They include the following [27] :
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Signs of right heart hypertrophy, in addition to abnormalities associated with the underlying defect
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Frontal plane QRS right-axis deviation
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Tall, monophasic R wave in V 1, deep S wave in V 6, ± ST and T wave abnormalities
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P pulmonale
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Atrial or ventricular arrhythmias can be seen in the presence of heart failure
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First-degree atrioventricular (AV) is common in AV septal defects
6-minute walk test versus cardiopulmonary exercise test
The 6-minute walk test (6MWT), which requires minimal equipment and subspecialty experience, is simpler than the more formal and involved traditional cardiopulmonary exercise test (CPET). Moreover, the 6MWT is better tolerated in younger children, who often will not comply with the multiple leads, facemask, or other equipment needed for a CPET.
The 6MWT may be effective in patients with a walk distance shorter than 300 m. In patients above the 300-m threshold, however, a CPET should be considered. [37]
In Eisenmenger syndrome during exercise, the systemic vascular resistance decreases substantially and the pulmonary vascular resistance decreases inadequately. Thus, pulmonary vascular resistance is more elevated during exercise than the systemic one, leading to very low oxygen saturations (< 50%), dyspnea, dizziness, marked cyanosis, and the patient stops exercising. [38, 39]
Cardiac Catheterization
Cardiac catheterization can be of value in patients with Eisenmenger syndrome, after collecting clinical and noninvasive data, to confirm and/or demonstrate the following:
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Severity of pulmonary arterial hypertension
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Conduit patency and pressure gradient
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Coexisting coronary artery anomalies (rare)
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Degree of shunting
Cardiac catheterization permits the examination of the intracardiac structure and exclusion of potentially reversible causes of pulmonary hypertension, as well as assessment of ventricular function, examination of the intracardiac shunt, determination of pulmonary artery pressure and flow, and calculation of pulmonary vascular resistance. Hemodynamic assessment has prognostic predictive value. In one study, diastolic pulmonary artery pressures of at least 45 mm Hg and World Health Organization (WHO) classification 3-4 were associated with progression of disease. [40]
Histology
In patients with Eisenmenger syndrome and severe pulmonary vascular disease, histologic analysis reveals abnormal extension of muscle into small peripheral arteries, severe medial smooth muscle hypertrophy of existing muscular arteries, plexiform lesions and increased intercellular material, and a reduction in the overall concentration and size of arteries.
Staging
In 1958, Heath and Edwards proposed a histologic grading of pulmonary vascular disease that corresponds to the duration and severity of injury caused by increased pressure and volume load. [12] This grading is a histopathologic classification derived from biopsies taken from isolated portions of the lung.
A biopsy of various segments of the lung could possibly be performed at the same time, yielding different histologic grades. Currently, performing lung biopsies is rarely necessary. The combination of pulmonary angiography and measurement of pulmonary vascular hemodynamics is usually sufficient to guide therapy.
Stages of pulmonary vascular pathology, according to the histopathologic criteria of Heath and Edwards, are as follows [12] :
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Stage I: Medial hypertrophy (reversible)
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Stage II: Cellular intimal hyperplasia in an abnormally muscular artery (reversible)
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Stage III: Lumen occlusion from intimal hyperplasia of fibroelastic tissue (partially reversible)
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Stage IV: Arteriolar dilatation and medial thinning (irreversible)
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Stage V: Plexiform lesion, which is an angiomatoid formation (terminal and irreversible)
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Stage VI: Fibrinoid/necrotizing arteritis (terminal and irreversible)
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Eisenmenger Syndrome. This radiograph reveals an enlarged right heart and pulmonary artery dilatation in a 24-year-old woman with an unrestricted patent ductus arteriosus (PDA) and Eisenmenger syndrome. RA = right atrium.
-
Eisenmenger Syndrome. Apical, 4-chamber, transthoracic echocardiographic view demonstrating an ostium primum atrial septal defect (ASD) with enlarged right-side chambers. RA = right atrium, RV = right ventricle, LA = left atrium, LV = left ventricle.
-
Eisenmenger Syndrome. This computed tomography (CT) chest scan shows a large, unrestricted patent ductus arteriosus (PDA) in a 24-year-old woman with Eisenmenger syndrome. Desc. aorta = descending aorta.
-
Eisenmenger Syndrome. This apical, 4-chamber, transthoracic echocardiographic segment shows color Doppler flow across the interatrial septum at the site of a large ostium primum atrial septal defect (ASD). RA = right atrium.
-
Eisenmenger Syndrome. This transesophageal echocardiographic image is from the midesophagus of a patient with Eisenmenger syndrome secondary to an unrestricted patent ductus arteriosus (PDA). It shows a severely dilated pulmonary artery (PA). Asc. Ao. = ascending aorta.
-
Eisenmenger Syndrome. This is a color Doppler interrogation of the tricuspid valve in a patient with Eisenmenger syndrome. It demonstrates an elevated estimated right ventricular systolic pressure of 106 mm Hg and right atrial pressure, reflecting pulmonary hypertension. TR = tricuspid regurgitation.
-
Eisenmenger Syndrome. This is a transthoracic Doppler examination of the pulmonic valve in a 24-year-old woman with Eisenmenger syndrome secondary to an uncorrected ostium primum atrial septal defect (ASD). It reveals an elevated estimated pulmonary artery diastolic pressure of 51 mm Hg and right atrial pressure. PR = pulmonic regurgitation.
