Eisenmenger syndrome is a condition that involves elevation of the pulmonary arterial pressure to the systemic level, and this is caused by increased pulmonary vascular resistance with reversal or bidirectional shunting through a large intracardiac or extracardiac congenital heart defect. Congenital heart disease represents one such disease that is commonly associated with PAH. Eisenmenger syndrome is on the extreme end of the spectrum of PAH in the setting of congenital heart disease.1)

In 1897 Victor Eisenmenger described the clinical and pathological features of Eisenmenger syndrome in a patient with a large ventricular septal defect. The current view of Eisenmenger syndrome was recognized by Paul Wood and others who, in the 1950s, described the underlying pathophysiology as "pulmonary hypertension with reversed central shunt" and they also described the clinical phenotype of Eisenmenger syndrome that includes very different cardiac malformations associated with severe PAH.1-3)

The concept of Eisenmenger syndrome is well understood, with its progressive pulmonary vascular disease and reversal of a shunt, and this represents a final pathway for several morphological cardiac defects. Nowadays, Eisenmenger syndrome can be prevented in most pediatric patients. There have been advances in imaging, surgery and intensive care facilities, and also advances in early definitive therapy for the majority of lesions associated with a risk of developing Eisenmenger syndrome, and so a progressive decrease in the prevalence of this disease may be expected. As the annual mortality rates of Eisenmenger patients are relatively low, identification of the risk factors for this disease is problematic.4)5)

However, when patients do present with established Eisenmenger syndrome, the treatment options are generally limited to palliative measures and only very selected subgroups of patients may be considered for heart-lung transplantation. Effective drugs for the treatment of pulmonary hypertension have recently become available. These therapies may also be applicable to patients with pulmonary hypertension associated with congenital heart disease, and so they will potentially improve their symptoms and prognosis. The preliminary results of applying these drugs to patients with Eisenmenger syndrome are promising. The recent advances in pharmacological therapies for pulmonary hypertension and the prospect of heart-lung transplantation for selected patients emphasize the importance of correctly selecting patients for such therapies, with a view to further improving both the quality and duration of survival.

PAH is defined as an elevated mean pulmonary arterial pressure(PAP) of >25 mmHg at rest or 30 mmHg on exercise(Table 1).6) PAH has traditionally been classified according to the presence or absence of an identifiable underlying cause into primary or secondary PAH, for example, PAH with congenital heart disease (Table 2).3) PAH with congenital heart disease occurs as a result of an unrepaired systemic to pulmonary communication from a congenital heart defect; thus, it might persist even though the postoperative period after corrective surgery for the defect. There are several types of congenital heart defects that are associated with an increased risk for the development of pulmonary vascular disease, e.g., ventricular septal defect, patent ductus arteriosus and atrioventricular canal defect. For patients with a large, nonrestrictive ventricular or arterial communication, the shunt volume and direction are mainly determined by the pressure difference between the systemic and pulmonary circulations. In contrast, patients with a large atrial communication may have a right-to-left shunt that is not necessarily due to the systemic or suprasystemic pulmonary arterial pressures, and the right-to-left shunting may rather reflect lower right ventricular compliance, which is a consequence of right ventricular hypertrophy. The natural course of patients with atrial communications is generally different. PAH displays high penetrance and the onset of Eisenmenger syndrome is relatively early, and this is the rule for patients with large shunts at the ventricular or arterial level. Yet the majority of patients with even large atrial septal defects do not develop Eisenmenger syndrome, and those who develop PAH often do so much later in life.

This disease complex was renamed "Eisenmenger syndrome" and it was defined as pulmonary hypertension at systemic levels that was caused by high pulmonary vascular resistance(>800 dynes · s/cm⁵) with reversed or bidirectional shunting through any large systemic to pulmonary communications. This classification implied irreversibility and inoperability for a subgroup of patients with congenital heart defects. Although there have been many advances in understanding of the pathophysiology of Eisenmenger syndrome and also advances in treating this disease, there is still no cure for this progressive condition once it is established, aside from lung or heart-lung transplantation, which is associated with significant morbidity and mortality.7-11)

Untreated or even treated Eisenmenger syndrome is characterized by a progressive increase in the pulmonary vascular resistance leading to right ventricular failure and death.

Three basic mechanisms cause pulmonary hypertension. These include 1) increased pulmonary blood flow into a normal vascular bed via increased cardiac output and left-to-right shunts, 2) increased resistance in the precapillary pulmonary vessels via constriction, obliteration and obstruction, and 3) abnormal resistance in the postcapillary vascular bed via pulmonary vein obstruction, left atrial obstruction(e.g., cor triatriatum and myxoma), mitral or aortic valve disease, and left ventricular dysfunction. Specific therapies can be directed at the patients' underlying diseases.5)12)

The main vascular changes of pulmonary arterial hypertension are 1) vasoconstriction, 2) smooth-muscle cell and endothelial-cell proliferation, and 3) thrombus formation in the pulmonary vessels.5-7) Thus, PAH is a dynamic and multifactorial process related to vasoconstriction and remodeling of the pulmonary vascular bed, which may be aggravated by thrombosis. These findings suggest the presence of perturbations in the normal relationships between vasodilators and vasoconstrictors, and these homeostatic imbalances are probably the consequence of pulmonary endothelial-cell dysfunction or injury.

High flow and high pressure of pulmonary artery may induce pulmonary vascular endothelial damage, leading to a loss of the endothelial barrier function. This may be associated with degradation of the extracellular matrix(activation of endogenous vascular elastase and matrix metalloproteinases) as well as to the release of growth factors(fibroblast growth factor and transforming growth factor-β). These factors induce smooth muscle cell hypertrophy and proliferation, resulting in extension of smooth muscle cells into the peripheral pulmonary vasculature, and smooth muscle cell migration with neointima formation. Furthermore, endothelial damage may result in adherence and activation of platelets and leukocytes, which favors immune inflammation and thrombosis as well as activation of the coagulation pathways.

Endothelial dysfunction also affects the production of vasoconstrictors(such as endothelin-1 and thromboxane) and vasodilators(such as nitric oxide, vasoactive intestinal peptide, and prostaglandin I₂), and this shifts the balance in favor of factors that induce vasoconstriction and ultimately pulmonary vascular remodeling.

Arachidonic acid metabolites such as prostacyclin and thromboxane A2 are active in the pulmonary vessels, and these are associated with vasodilation and vasoconstriction.

Prostacyclin is a platelet inhibitor and it's capable of inhibiting endothelial cell proliferation, whereas thromboxane A2 is a platelet activator.

Endothelin-1 is a vasoconstrictor that causes smooth muscle proliferation in pulmonary vessels. Vasodilation is induced by NO, which is produced by endothelial cells through a cGMP-dependent pathway, and NO additionally inhibits platelet function and smooth vessel proliferation. In patients with PAH, there are imbalances of these potent vasoactive factors, as well other vasoactive compounds such as vascular endothelial cell growth factor, adrenomodullin, serotonin and vasoactive peptides. Patients with PAH have been found to have altered homeostatic balances of these mediators, tending towards a prothrombotic, vasoconstrictive physiology. These acquired alterations in the normal vascular physiology contribute to the onset of PAH. Other conditions like chronic hypoxemia and small vessel thrombosis can contribute to chronic changes of vasoconstriction in the pulmonary vasculature.

PAH is characterized by elevated pulmonary vascular resistance. In patients with large left-to-right shunts, the pulmonary vascular bed is subjected to ongoing shear stress. For patients with a large unrestrictive defect, the pulmonary and systemic systolic arterial pressures are the same. This leads to the histopathologic changes seen in PAH patients, which include pulmonary arteriolar medial hypertrophy, intimal fibrosis and plexiform lesions. Medial fibrosis and necrotizing arteritis changes eventually arise in the pulmonary vessels, as were described by Heath and Edwards for PAH patients with secondary congenital septal defects. It has been suggested that these histological changes may correlate with the clinical severity of PAH. For patients with Eisenmenger syndrome, these chnages may be due to the increased flow across the pulmonary vascular bed that causes peripheral extension of muscle from differentiating pericytes and intermediate cells in the precapillary vessels, as well as to damage to the pulmonary vascular endothelium, which sets in motion a series of events at the cellular level. The pulmonary vascular resistance increases with endothelial dysfunction and this ultimately causes a decrease in left-to-right shunting. Eventually, when the resistance becomes significantly elevated, the shunting becomes bidirectional and then it becomes right-to-left. The long-term follow up for those patients with elevated pulmonary vascular resistance and they have undergone closure of their defect is worse than that for the unrepaired, Eisenmenger syndrome patients with the same lesion. This may be related to the absence of a communication between the right and left circulations that may serve as a "pop-off valve" in patients who are at risk for pulmonary hypertensive crises. Normal right atrial pressures have been demonstrated in patients with Eisenmenger syndrome, suggesting that the right atrial pressure remains normal at the expense of the right to left shunt, i.e., desaturation. In addition, the systemic cardiac output is greater in patients with Eisenmenger syndrome than that in those patients with primary pulmonary hypertension, which is presumably secondary to the presence of the "pop off valve." Finally, right-sided heart failure may develop in all the patients with PAH.

For the genetic background, 6% of patients with PAH-associated congenital heart disease were found to have bone morphogenetic protein receptor type 2 missense mutations; this frequency was comparable with that reported for patients with anorexigen-associated PAH(8%), but it was considerably lower than that observed for patients with idiopathic or familial PAH(26% and 50%, respectively). This is likely to reflect the complex interrelationship between genetic susceptibility and environmental factors, such as the pulmonary blood flow or pressure, in the etiology of PAH associated with congenital heart disease.8-10)

Early diagnosis and treatment for a large systemic-to-pulmonary shunt is critical for preventing Eisenmenger syndrome. The treatment options for patients with PAH associated with congenital heart disease are limited to palliative measures and heart-lung transplantation for highly selected patients with Eisenmenger syndrome. The treatment may include the use of supplemental oxygen, digitalis, diuretics, vasodilators and anticoagulants, or lung transplantation and repair of the congenital heart defect(s), or heart-lung transplantation.11)12)24-29)

There is no cure for PAH, but the medical treatment has recently improved dramatically, offering both relief from symptoms and prolonged survival. The mainstays of current medical therapy fall into several classes, including vasodilators, anticoagulants, antiplatelet agents, antiinflammatory therapies and vascularremodeling therapies. Many of the most effective agents have pleiotropic effects. Epoprostenol is a vasodilator, a platelet inhibitor and an antiinflammatory agent, whereas the endothelin-receptor antagonist bosentan is a vasodilator, an antiinflammatory agent and a remodeling mediator.

Patients with Eisenmenger syndrome must avoid circumstances that may exacerbate their pulmonary vascular disease.

Exercise should be guided by the patients' symptoms with strict limits adhered to. Avoidance of travel to high altitude, although air travel is permitted, should be advised because of the potential for alveolar hypoxia leading to further pulmonary arterial vasoconstriction and worsened symptoms.

Pregnancy, oral contraceptives and hormone replacement therapies should be avoided because of the increased risk of thromboembolic events. Pregnancy can be fatal for patients with PAH both during the course of delivery and postpartum.

Pulmonary vasodilator therapy has been used and this is based on the treatment of primary pulmonary hypertension(PPH). The main concept is that pulmonary vasoconstriction plays a role in the development of the pulmonary vascular disease. Although the mechanisms may be different for patients with Eisenmenger syndrome compared with PPH patients, there is now evidence that patients with Eisenmenger syndrome may also benefit from vasodilator and/or antiproliferative therapies such as intravenous epoprostenol and Bosentan, which were previously reserved for PPH patients.

Before initiation of pulmonary vasodilator therapy, patients should undergo cardiac catheterization: (1) to assess the "operability" and (2) for acute pulmonary vasodilator testing in those patients who are considered inoperable, i.e., Eisenmenger syndrome as above. If a patient responds to acute vasodilator testing with a decrease in the pulmonary vascular resistance of ≥30% after the administration of inhaled nitric oxide (10-80 ppm) or intravenous epoprostenol and a similar response is demonstrated to acute testing with sublingual CCB, then they can be offered treatment with long-term oral CCBs if they are not in significant right heart failure. This is based on previous studies for patients with PPH who demonstrate acute pulmonary vasoreactivity and subsequent clinical and hemodynamic improvement as well as increased survival with long term administration of oral CCBs. Yet a significantly lower acute response rate was demonstrated for patients with PAH associated with congenital heart defects as compared to that for patients with PPH. In a small study, only 7% of the 94 patients with pulmonary hypertension associated with congenital heart defects responded to acute vasodilator testing.

The two options are atrial septostomy and lung or heart-lung transplantation.

The cause of death for the majority of the follow-up studies on Eisenmenger syndrome has displayed two distinct patterns. One set of patients appears to develop progressive heart failure, which is the cause of death, whereas a second set dies suddenly. The patients dying from heart failure appears to be increasing in comparison with sudden death in the recent studies.

Hemoptysis, which was the cause of death in an earlier era, remains a common cause of clinical morbidity, but not of death. The third important observation is that patients with Eisenmenger syndrome associated with complex heart disease die sooner than those with simple lesions, and it can be anticipated that the cardiac function may be relatively well preserved for longer periods in patients with simple lesions.

For the mechanisms of sudden death in young patients, either those with normal hearts or those with previous operations for congenital heart disease, acute arrhythmia is increasingly being recognized to be the terminal event. Ventricular tachycardia or fibrillation was noted in the patients for whom an electrocardiogram was recorded during the terminal event. It would be reasonable to suspect that sudden deaths in the Eisenmenger population could be arrhythmic in origin. Supraventricular or ventricular arrhythmia may produce acute worsening of the cardiac performance and CO, and so lead to death.

The risk factors associated with a failing heart are currently better understood. A higher NYHA functional class and the clinical and laboratory parameters of heart failure are predictors of mortality. The age at clinical presentation is also a risk factor and it may be presumed that younger patients have more severe disease or rapid progression. The degree of hypoxemia is also correlated with the NYHA functional class and it is associated with a poorer prognosis, as is an elevated right atrial mean pressure, which probably reflects ventricular failure.

Sustained arrhythmias, be they supraventricular or ventricular, have been documented on routine electrocardiograms or 24-h Holter monitoring, and previously documented arrhythmia was indeed a marker for death. Some symptoms like palpitations and syncope appeared to be relatively common in the Mustard/Senning study, and they were predictive of sudden death. Syncope was associated with a poor outcome. Alterations in the baseline electrocardiogram, which may reflect abnormal depolarization or repolarization, could be predictors of death. It is clear that patients with Eisenmenger syndrome should be aggressively monitored for diagnosing potentially lethal arrhythmias and any symptoms of arrhythmia warrant careful follow-up with serial long-term Holter recordings. In patients with documented sustained arrhythmia, aggressive therapy with antiarrhythmia medications, pacing or even an implantable defibrillator may be considered. Selective pulmonary vasodilator therapy can be done for patients with increasing heart failure consequent to the progression of pulmonary vascular disease, as there is some evidence that this is also beneficial in the Eisenmenger population. For patients with suspected or documented arrhythmia, arrhythmia prevention strategies should take precedence, if achievable, and this would be of obvious benefit.30-34)

Some studies34) have shown a predicted median survival of 52.6 years for adult patients with the Eisenmenger syndrome. These patients may survive into their third or fourth decade if managed appropriately. The survival rates at 30, 40, and 55 years of age were 75%, 70%, and 55%, respectively. Compared with PPH, survival is clearly better for PAH patients with congenital heart disease. PPH represents a life-threatening disease with a devastating prognosis and a reported median survival of 2.8 years. Several potential mechanisms account for this superior prospect of survival compared with PPH. First, in PAH patients with congenital heart disease, the right ventricle is subjected to high pressures from birth or from infancy, and so it may be better trained to support the systemic pulmonary pressures, which can reduce the incidence of early right ventricular failure. Second, in patients with PPH, the pulmonary hypertension itself limits the pulmonary blood flow and thereby it reduces the systemic blood flow during exercise. Patients with PAH-associated shunts maintain or increase their systemic cardiac output during exercise via right to left shunting.25)34)

PAH is, to a variable degree, associated with congenital heart disease, and this depends on the size and location of the underlying cardiac defect, as well as on the repair status. Eisenmenger syndrome is at the extreme end of PAH that presents with or without reversed shunting and associated cyanosis. The prospects for survival have improved for patients with Eisenmenger syndrome in the current era. The great advances in operative skill and medical treatment, such as the new vasodilators, allow young patients with congenital heart defects to undergo early diagnosis and early corrective surgery. Eisenmenger syndrome has previously implied irreversibility and inoperability for a subgroup of patients with PAH and congenital heart defects. Today, although there have been many advances in understanding the pathophysiology of Eisenmenger syndrome and also advances in treating this disease, there is still no cure for this progressive condition once it is established, aside from lung or heart-lung transplantation, which is associated with significant morbidity and mortality. The newly developed vasodilators are well tolerated and they improve the exercise capacity and hemodynamics without compromising the peripheral oxygen saturation in patients with Eisenmenger syndrome.