INTRODUCTION — The triad of systemic-to-pulmonary congenital cardiovascular communication, pulmonary arterial disease, and cyanosis is called Eisenmenger syndrome. The diagnosis of Eisenmenger syndrome implies that pulmonary arterial disease has developed as a consequence of increased pulmonary blood flow and requires exclusion of other causes of pulmonary hypertension.

In 1897, Eisenmenger described a syndrome in which pulmonary vascular disease developed in patients with a nonrestrictive ventricular septal defect [1]. It was subsequently shown that pulmonary vascular disease could also occur with other congenital cardiac defects in which a systemic-to-pulmonary communication is present, such as atrial shunts, other ventricular shunts, and aortic shunts (table 1).

Such conditions are often associated with an initial left-to-right shunt. Increased pulmonary blood flow as a result of the shunt leads to the development of pulmonary vascular disease with increased pulmonary vascular resistance. The shunt may then reverse and become right-to-left (figure 1A-B and algorithm 1) [2,3]. At this stage, the patient typically becomes cyanotic.

With the advent of surgical correction of congenital heart disease (CHD), the prevalence of Eisenmenger syndrome has declined but is not negligible. This topic will review the general features, evaluation, and prognosis of CHD-related pulmonary arterial hypertension and Eisenmenger syndrome. The pathology and pathophysiology of pulmonary arterial hypertension in Eisenmenger syndrome are discussed in detail separately. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)".)

The medical management of patients with Eisenmenger syndrome is discussed separately. (See "Management of Eisenmenger syndrome".)

GENERAL FEATURES — The diagnosis of Eisenmenger syndrome requires the presence of congenital heart disease (CHD). In some cases, the diagnosis is not established until adulthood, after the development of symptoms or even overt features of pulmonary hypertension such as syncope, atrial and ventricular arrhythmias, cyanosis, and as late findings, both right and left heart failure.

Anatomy and physiology — The development of Eisenmenger syndrome may accompany a variety of forms of CHD. In one study of 201 patients, the most common defects were ventricular septal defects (33 percent), atrial septal defects (30 percent), and patent ductus arteriosus (14 percent) [4]. Other disorders, including complex anatomic abnormalities, can also be associated with the Eisenmenger syndrome. In all cases, a communication between the systemic and pulmonary circulations is present. In some conditions, 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.

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) is normal in utero, and the high pulmonary vascular resistance (PVR) of the fetus limits left-to-right shunting. In the postnatal period, there is normally a rapid decline in PVR and an increase in right ventricular compliance, resulting in a left-to-right shunt and an increase in pulmonary blood flow.

In most patients with systemic-to-pulmonary communications, shunting occurs to some degree in both directions. This is not surprising since, during the cardiac cycle, there are changes in intrathoracic pressure associated with respiration, and changes in venous return associated with exercise, changes in position, and other factors. As a result, the pressure gradient across such communications varies with time. 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 extra 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 leads to pulmonary vascular disease (picture 1) and increased PVR. The increase in PVR results in a rise in pulmonary artery pressure which is called "pulmonary arteriolar hypertension" (PAH) to emphasize the etiologic influence of disease in the pulmonary arterioles. PAH causes reversal of the shunt and net right-to-left shunting (Qp:Qs <1) (algorithm 1). With shunt reversal, venous blood returning to the right side of the heart passes through the communication, reducing the oxygen saturation of the arterial blood in the left heart and causing cyanosis. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)".)

Shunt size and defect type — The risk of developing Eisenmenger syndrome appears to be determined by the size of the initial left-to-right shunt and the volume of pulmonary blood flow, with larger shunts having increased risk. In addition, the type of defect is important. Only approximately 10 percent of patients with unrepaired atrial septal defects develop Eisenmenger syndrome, compared with 50 percent of patients with unrepaired ventricular septal defects and nearly all patients with unrepaired truncus arteriosus [5].

Eisenmenger syndrome has been documented in some patients who never manifested a large left-to-right shunt [6,7]. In fact, it is unusual for the evolution of the syndrome to be documented clinically (especially given the currently available approaches to managing known left-to-right shunts). The temporal pathophysiologic sequence outlined above (algorithm 1) has therefore been called into question; in most patients diagnosed with Eisenmenger syndrome, PAH, right-to-left shunting, and cyanosis are found at initial presentation.

Physical examination — Physical examination of the patient with Eisenmenger syndrome demonstrates central cyanosis and digital clubbing (figure 2 and picture 2). Most affected patients have diffuse central cyanosis, and clubbing involves all extremities equally. However, in some cases the pattern and degree of cyanosis and clubbing may depend upon the patient's hemodynamic status and the cardiac anatomy. An often discussed 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 can result in differential cyanosis and clubbing that may be more pronounced in the lower extremities.

The cardiovascular examination reveals findings consistent with the presence of PAH. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

Early physical signs include:

●The jugular venous pulse is usually normal when the shunt is distal to the tricuspid valve. In other cases, a prominent A wave is seen, due to right atrial contraction that generates a high pressure in order to fill the hypertrophied right ventricle (figure 3). (See "Examination of the jugular venous pulse".)

●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 dilatation 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 "Examination of the jugular venous pulse".)

●The increase in venous pressure and/or neurohormonal activation can lead to peripheral edema, hepatomegaly, and ascites [8,9].

●Murmurs of tricuspid and pulmonic regurgitation become audible and occasionally palpable. Tricuspid regurgitation in this setting is secondary to dilatation of the tricuspid annulus and right ventricle, and is not a sign of primary valve disease [10]. (See "Auscultation of cardiac murmurs in adults" and "Etiology, clinical features, and evaluation of tricuspid regurgitation".)

PROGNOSIS — The mean age at death of patients with Eisenmenger syndrome has been reported to be 37 years or less, although the individual clinical course is quite variable and these data precede routine use of pulmonary vasodilators. Most patients are thought to die from progressive cardiovascular disease and heart failure, from sudden cardiac death, or from intrapulmonary hemorrhage due to rupture of a major vessel [4,11,12]. Although some patients with Eisenmenger syndrome survive into their 60s and beyond [11-15], survival is generally limited.

A systematic review included 12 studies of 1131 patients not treated with advanced therapy for pulmonary hypertension and adjusted for immortal time bias found in many reports; the adjusted 10-year mortality rates ranged between 30 and 40 percent [16]. Although mortality rates in the 1950s and 1960s were worse, similar mortality rates were observed in patients studied from the 1970s to the 2000s.

In a later multicenter study of 1098 patients (median age 34.4 years, range 16.1 to 84.4 years), with median follow-up of 3.1 years, significant predictors of death on multivariable analysis included age (hazard ratio [HR] 1.41/10 years, 95% CI 1.24-1.59), pretricuspid shunt (HR 1.56, 95% CI 1.02-2.39), and presence of pericardial effusion (HR 2.41, 95% CI 1.59-3.66); lower risk was seen with higher oxygen saturation at rest (HR 0.53/10 percent, 95% CI 0.42-0.64) and with sinus rhythm (HR 0.53, 95% CI 0.32-0.88) [15].

Smaller earlier studies found that patients with complex congenital heart disease had earlier clinical deterioration (eg, mean age 19 versus 27 years [12]) and shorter survival (eg, mean age 26 versus 33 years [12]) than those with simple congenital heart disease. In a series of 171 patients with Eisenmenger syndrome, median survival was reduced by approximately 20 years in those with simple underlying lesions and by approximately 40 years in those with complex lesions compared with healthy individuals [14]. Predictors of mortality included functional class, signs of heart failure, history of clinical arrhythmias, QRS duration and QTc interval, low serum albumin, and low potassium levels. Hemoptysis is common (20 percent in one series) but may not affect prognosis [12].

However, patients with Eisenmenger syndrome have a better life expectancy than patients with primary pulmonary hypertension (PPH) who have similar hemodynamics [17,18]. This was illustrated in a report of patients with severe pulmonary arteriolar hypertension (37 Eisenmenger, 57 PPH) [17]. Actuarial survival at one and three years of those not receiving transplants was higher in those with Eisenmenger syndrome (97 versus 77 percent and 77 versus 35 percent, respectively). This difference may be related, in part, to the preservation of biventricular function in patients with Eisenmenger syndrome, with the potential for biventricular sharing of the hemodynamic loading conditions [19]. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

EVALUATION FOR CONGENITAL HEART DISEASE RELATED PULMONARY ARTERIAL HYPERTENSION

Initial evaluation — We agree with the 2008 American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommendations for the following noninvasive assessment in all adult congenital heart disease (CHD) patients with suspected pulmonary artery hypertension (PAH) [20]:

●Pulse oximetry, with and without administration of supplemental oxygen, as appropriate. Finger and toe oximetry in those with suspected Eisenmenger syndrome.

●Electrocardiogram (ECG) – The ECG may demonstrate right or biventricular hypertrophy with associated ST-T wave changes (waveform 1). There may also be evidence of a right atrial abnormality (a tall, narrow P wave) (waveform 2 and waveform 3). (See "ECG tutorial: Chamber enlargement and hypertrophy".)

●Chest radiograph – The chest radiograph usually shows dilatation of the 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 [21]; right heart enlargement; and right ventricular hypertrophy (image 1).

●Complete blood count and nuclear lung scintigraphy.

●Cardiovascular imaging via transthoracic echocardiography (TTE) and, when needed, additional imaging with transesophageal echocardiography (TEE), cardiovascular magnetic resonance (CMR) imaging, or CT.

•Imaging findings can include signs of chronic right ventricular pressure overload. The elevation in pressure leads to increased right ventricular wall thickness with paradoxical bulging of the septum into the left ventricle during systole. With more advanced disease, right ventricular dilatation and hypokinesis occur, the septum shows abnormal diastolic flattening, and right atrial dilatation and tricuspid and pulmonic regurgitation are seen (movie 1 and movie 2).

•Imaging also 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). Delineation of the cardiac defect may be difficult with TTE due to equalization of pressures in the right and left heart.

•Two-dimensional echocardiography may be limited by poor acoustic windows in patients with PAH. TEE should be considered in patients with suboptimal transthoracic images presenting with PAH, in an effort to exclude CHD. TEE may be contraindicated in some patients given the potential risk of sedation. Agitated saline contrast can be helpful in confirming a suspected intracardiac shunt but should be avoided when a large intracardiac shunt has been established. (See "Management of Eisenmenger syndrome", section on 'Noncardiac surgery'.)

•CT and CT angiography of the pulmonary arteries can reveal enlargement, thrombosis, and mural calcification of the pulmonary trunk and its proximal branches [22,23]. Within the lung parenchyma, embolic infarction, hemorrhage, neovascularity, lobular ground glass opacification, and hilar and intercostal collaterals may also be seen [21]. 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 [21]. These lesions are more common and more severe with posttricuspid right-to-left shunts at the level of the ventricles or great arteries.

Additional testing — If PAH is identified but its cause is not recognized, additional testing should include the following [20]:

●Pulmonary function tests with volumes and diffusion capacity (diffusing capacity of the lung for carbon monoxide).

●Overnight oximetry to screen for obstructive sleep apnea.

●Pulmonary embolism protocol CT with parenchymal lung windows or ventilation perfusion scan.

●Additional testing as appropriate to rule out contributing causes of PAH.

●A six-minute walk test or similar exercise test may be considered as part of the functional assessment. This also provides information about oxygen saturation with exercise.

●Cardiac catheterization at least once, with potential for vasodilator testing or anatomic intervention, at a center with expertise in catheterization, PAH, and management of CHD-PAH. Cardiac catheterization enables characterization of the cardiac shunt and determination of pulmonary vascular resistance (PVR) and responsiveness to vasodilators. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)

There are a multitude of factors that 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 it may not necessarily fall in proportion to the reduction in shunt and pulmonary blood flow.

Additional evaluation for suspected Eisenmenger syndrome — Evaluation of suspected Eisenmenger syndrome includes a detailed history for all past medical and surgical interventions, thorough understanding of past and current anatomy, and evaluation of degree of PAH, ventricular function, and any secondary complications [20].

Evaluation should include all the above initially and additional testing plus ferritin and iron studies, renal and hepatic function tests, and six-minute walk testing.

Lung biopsy is not routinely used in diagnosing Eisenmenger syndrome. This was previously performed to determine the degree of pulmonary vascular disease. However, it is now recognized that this information can be obtained by noninvasive methods and the procedural risks exceed the benefits. However, when a biopsy is obtained, characteristic histologic features are seen (picture 1) [24,25]. The histologic grading of pulmonary vascular disease in patients with CHD is discussed separately. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Congenital heart disease'.)

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

●Eisenmenger syndrome is the triad of congenital systemic-to-pulmonary cardiovascular communication, pulmonary arterial disease causing severe pulmonary hypertension, and cyanosis. The development of pulmonary arterial disease is a consequence of increased pulmonary blood flow and requires exclusion of other causes of pulmonary hypertension.

●Physical examination of the patient with Eisenmenger syndrome generally demonstrates central cyanosis and digital clubbing. Common findings include a right ventricular impulse and a palpable pulmonary closure sound (P2).

●Life expectancy is generally more severely reduced in patients with Eisenmenger syndrome with complex congenital heart disease (CHD) than in patients with Eisenmenger syndrome with simple lesions such as ventricular septal defect, atrial septal defect, and patent ductus arteriosus.

●Patients with Eisenmenger syndrome have a better life expectancy than patients with pulmonary arterial hypertension (PAH) who have similar hemodynamics.

●Evaluation for CHD-related PAH should include noninvasive assessment of cardiopulmonary anatomy and function. If evaluation by cardiac catheterization is indicated, the procedure should be performed in a center with expertise in managing CHD-related PAH.

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.