Eisenmenger Syndrome in Adults: Strategies to Correct Congenital Defects Before Fixed Vascular Disease Develops

Congenital heart defects (CHDs) associated with large systemic-to-pulmonary shunts, (eg, atrial septal defect, ventricular septal defect, patent ductus arteriosus) can lead to pulmonary vascular disease, which is characterized by bidirectional shunting or reversal of the shunt. This phenomenon, which is associated with progressive cyanosis, polycythemia, and ultimately, functional limitation, was first described in 1897 by Viktor Eisenmenger and later termed the Eisenmenger syndrome (ES). If it is not corrected before fixed vascular disease develops, the patient is a poor surgical candidate as the failing right ventricle cannot tolerate closure of the defect. Approximately one third of all patients with CHD who have not undergone corrective procedures or who die of other causes, will die from pulmonary vascular disease.1 The course of the disease, however, is usually more favorable than for patients with primary pulmonary hypertension (PPH). Today, while there have been many advances in our understanding of the pathophysiology and treatment of ES in adults, 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.2The natural history of ES is highly variable, although overall survival is significantly better than for patients with PPH. Actuarial survival without transplantation is 97% at 1 year, 89% at 2 years, and 77% at 3 years for patients with ES and 77%, 69%, and 35%, respectively, for patients with PPH,3 (Fig 1). Most patients survive into the third to fourth decade of life, and there are rare case reports of patients living into the seventh decade. The Second Congenital Heart Disease Natural History Study (1993) demontrated that patients with ES can survive for several decades following diagnosis. In this study, 54% of 98 unoperated patients with ventricular septal defects and ES were alive 20 years after diagnosis.4 Further, in a retrospective study of 109 adults with ES, the median survival was 52.6 years of age.5 Some risk factors that have been associated with earlier mortality in ES patients have included trisomy 21, syncope, hemoptysis, elevated right atrial (RA) pressure, lower systemic arterial oxygen saturation, supraventricular arrhythmia, earlier age at presentation, electrocardiographic evidence of RVH, poor functional class, pregnancy, and ventricular or aortopulmonary shunt vs intraatrial shunt.5–7The pathophysiologic mechanisms, which lead to the histopathologic changes seen in ES, are not completely understood. Increased shear stress, flow, and pressure contribute to the pathobiology of pulmonary vascular disease. In patients with large left-to-right shunts, the pulmonary vascular bed is subjected to ongoing shear stress. This leads to the histopathologic changes seen in pulmonary arterial hypertension (PAH), which include pulmonary arteriolar medial hypertrophy, intimal fibrosis, and plexiform lesions (Figs. 2, 3).In ES patients, this may be the result of increased flow across the pulmonary vascular bed causing peripheral extension of muscle from differentiating pericytes and intermediate cells in precapillary vessels. In addition, damage to the pulmonary vascular endothelium from a mechanical stretch injury sets a series of events in motion at the cellular level (implicated in the pathogenesis of pulmonary vascular disease).68 As a result of these events, pulmonary vascular resistance increases and ultimately leads to a decrease in left to right shunting. Eventually, when the resistance becomes significantly elevated, shunting becomes bi-directional and at later stages becomes predominantly right to left. The long-term outlook for patients with elevated pulmonary vascular resistance who undergo closure of their defect(s) is worse than for unrepaired ES patients with the same lesion(s).9 This may be related to the absence of a communication between the right and left circulations, which may serve as a “pop-off valve” in patients who are at risk for pulmonary hypertensive crises.10 Systemic cardiac output is greater in patients with ES than in those with PPH, presumably secondary to the presence of their pop-off valve. In contrast to PPH patients, right ventricular function is typically preserved and heart failure is uncommon in patients with ES, until the end stages of the disease.1112Clinical History/Symptoms: Timely diagnosis of a large systemic to pulmonary shunt is critical in the prevention of ES. Defects closed within the first two years of life are unlikely to lead to pulmonary vascular obstructive disease.4 Infants with large, unrestrictive defects usually present initially with signs of congestive heart failure, and failure to thrive. Following years of continued exposure to high shear stress from the left to right shunting, the pulmonary vascular resistance increases, usually to systemic levels, leading to reversed shunting. Cyanosis then follows, which can be severe. In rare cases, the history of congestive heart failure or failure to thrive in infancy is absent. In these patients, reversal of flow may have occurred within the first two years of life. This group may represent a subset of patients who may have never had the normal physiologic fall in the pulmonary vascular resistance after birth or perhaps may represent a subset of patients with an increased susceptibility to pulmonary vascular disease.Eventually, all adults with ES develop cyanosis and suffer from some of its inherent complications, eg, polycythemia, headaches, blurry vision, cerebral abscesses and/or strokes. In addition, most patients develop progressive shortness of breath, dyspnea on exertion, and exercise intolerance. Patients may also complain of chest pain. Hemoptysis is more common with advancing age.On physical examination, ES patients may appear cyanotic at rest. In the early stages of the disease, they may only develop cyanosis with exertion. Virtually all ES patients will become progressively more cyanotic with exertion. Clubbing of the digits may be present. Most patients have normal jugular venous pressure on physical examination. On cardiac examination a right ventricular lift, a loud, palpable single S2, a high-pitched diastolic murmur of pulmonary insufficiency, and a pansystolic murmur of tricuspid insufficiency may also be present. If there is congestive heart failure, peripheral edema, ascites, and hepatosplenomegaly may be present.The electrocardiogram in patients with ES typically demonstrates right axis deviation and right ventricular hypertrophy. A right ventricular strain pattern may also be present, with associated ST-T segment changes (Fig 4). The chest x-ray may demonstrate right ventricular enlargement and enlarged central pulmonary arteries with “pruning” of the peripheral pulmonary vessels. The peripheral pruning is usually a late finding. The central pulmonary arteries often appear severely enlarged in patients with atrial septal defects. Two-dimensional echocardiography may demonstrate any of the following: a dilated right ventricle and atrium, right ventricular hypertrophy, diminished right ventricular function, tricuspid regurgitation, pulmonary insufficiency, flattening or posterior bowing of the interventricular septum, and bidirectional or right-to-left shunting across the cardiac defect.Right and left heart catheterization may be performed to assess “operability”. The patient is usually considered “inoperable” if the pulmonary vascular resistance is greater than 10 Wood units /m2 despite the administration of acute pulmonary vasodilator agents such as inhaled nitric oxide, intravenous epoprostenol, intravenous adenosine, or inhaled iloprost.Laboratory testing should include hemoglobin, hematocrit, and iron studies to determine the extent of polycythemia and need for supplemental iron. A coagulation profile should be performed at baseline prior to consideration of anticoagulation.Although the etiology and natural history of PPH and ES are different, the histopathologic changes are virtually identical. This has prompted adaptation of some of the treatment strategies for PPH for ES patients.Supplemental oxygen: Supplemental oxygen therapy should be considered for patients with ES. Although recent data from one small study demonstrated that supplemental oxygen did not offer a survival benefit for adult patients with ES,13 previous studies have demonstrated that the use of supplemental oxygen in children with pulmonary vascular disease during sleep may slow the progression of polycythemia.14 There is also evidence that desaturation may occur in the supine position because of VQ mismatch15 and that the use of supplemental oxygen attenuates these changes.In addition, patients who have significant desaturation with activity during exacerbations of heart failure, infections, or air travel because of increased oxygen extraction, in the setting of fixed oxygen delivery, may benefit from supplemental oxygen during exercise.Digitalis and diuretics: The efficacy of inotropic agents for right-heart failure remains controversial. There have been reports of increased cardiac output with the use of digitalis in patients with PPH.16 Thus, there may be a role for digitalis for ES patients with diminished right ventricular function.Diuretics may be useful for patients with ES and severe right-heart failure to relieve hepatic congestion and/or increased intravascular volume.Anticoagulation: Patients with ES are at risk for thromboembolic events and even a small pulmonary embolus can be life-threatening in patients who cannot vasodilate or recruit additional pulmonary vessels normally. Although there have been no adequate studies to demonstrate the efficacy of anticoagulation for patients with ES, most experts recommend anticoagulation; however, the risk of bleeding, particularly hemoptysis, needs consideration. If warfarin is used, the aim is to maintain the international normalized ratio (INR) at 1.5 to 2.0 for most patients, with a higher INR for patients who are hyper-coagulable.Phlebotomy: Phlebotomy with replacement of fluid may be helpful for cyanotic CHD beyond infancy in which severe hypoxemia has led to a large increase in red cell mass. When a hematocrit reaches the 65% to 70% range, or if the patient is symptomatic with a lower hematocrit, eg, blurry vision or headaches, exchange transfusion with plasma or crystalloid is indicated to lower the hematocrit to the 50% to 60% range. This must be done carefully since simply removing blood can decrease systemic vascular resistance and result in a sudden hypoxic event. Fortunately, many patients with ES tend to stabilize their hematocrit in the 60% to 65% range for many years or even decades, and no longer require phlebotomy. One must also follow iron stores, which often become depleted, leading to a decrease in the circulating blood volume and increased viscosity.17 Supplemental iron therapy is indicated for iron deficiency even if a patient is polycythemic to avoid a hyperviscosity syndrome related to iron deficiency in the setting of polycythemia.Vasodilator/antiproliferative therapies: Pulmonary vasodilator therapy has been used for the treatment of PPH based on the premise that pulmonary vasoconstriction plays a role in the development of the pulmonary vascular disease. Patients with ES may also benefit from vasodilator/antiproliferative therapies such as intravenous epoprostenol, previously reserved only for PPH patients18 (Table).In our center, prior to initiation of pulmonary vasodilator therapy, ES patients undergo cardiac catheterization with acute pulmonary vasodilator testing. If patients respond to acute vasodilator testing with a fall in pulmonary vascular resistance of >30% following the administration of inhaled nitric oxide (80 ppm) or intravenous epoprostenol, and demonstrates a similar response to acute testing with sublingual calcium channel blockade, they can be offered treatment with long-term oral calcium channel blockade, if they are not in significant right-heart failure (mean RAP > 15 mmHg, C.I.<1.5 L/min/m2). This is based on previous studies of patients with PPH that demonstrate acute pulmonary vasoreactivity and subsequent clinical and hemodynamic improvement, as well as increased survival with long-term oral calcium channel blockade.19 It should be noted that our experience has demonstrated significantly lower acute response rates for ES patients than for patients with PPH. In a small study from our institution, only 7% of 94 patients (including 27 adult patients) with PAH associated with CHD responded to acute vasodilator testing.20 None of the “responders” were adult patients. For those symptomatic patients with ES who do not respond to acute vasodilator testing, treatment options include long-term intravenous epoprostenol therapy or lung or heart-lung transplantation.Continuous intravenous epoprostenol therapy has been used successfully in patients with PAH and associated CHD. In a report from our institution of 20 patients (including 6 adult patients) with PAH associated with CHD (10 operated and 10 with residual shunts), who were not responsive to acute vasodilator testing, there were improved hemodynamics, and quality of life following one year of treatment with continuous intravenous epoprostenol.18 Notably, in patients with residual shunts, we did not see an increase in right-to-left shunting, nor did we see a fall in systemic arterial blood pressure with long-term epoprostenol. These 10 patients with residual shunts had a significant improvement in oxygen delivery while receiving long-term epoprostenol.18 McLaughlin et al, also reported improved hemodynamics with continuous intravenous epoprostenol in a study of patients with PAH that included 7 patients with CHD.21 Unfortunately, the use of continuous intravenous prostacyclin has several associated risks, including the risk of thromboembolic events to the systemic circulation in the setting of ongoing pulmonary-to-systemic shunting. Although the data are limited, for patients with CHD, an alternative to continuous intravenous epoprostenol is the use of a subcutaneous prostacyclin analogue, such as treprostinil,22 which avoids the risks associated with a central venous catheter.While successful heart-lung transplantation and lung transplantation with repair of CHD have been available for over 20 years, there are several limitations to these procedures. Patients with ES have the highest perioperative mortality and the lowest 1-month survival rates among all lung transplant recipients.23In addition, a limited number of centers can perform the procedures and care for the patients following transplantation, and the availability of suitable donors is limited. Further, the high incidence of bronchiolitis obliterans in the transplanted organs of these patients (25 to 40%) is of great concern.23 For at least 5 years, single and bilateral lung transplantations have been performed increasingly in patients with pulmonary vascular obstructive disease including patients with severe right ventricular failure.2 Thus, lung transplantation with repair of the CHD appears to be the surgical procedure of choice for virtually all patients in whom left ventricular function is maintained despite severe right ventricular failure. Currently, the overall 1-year, 5-year, and long-term (9-year) survival for lung transplantation for recipients with all forms of lung disease is 71%, 49%, and 20%, respectively. For patients with ES, the 1-year and 5-year survival following lung transplantation is worse, 52% and 39% respectively.23 Recent data suggest that patients with ventricular septal defects have the best prognosis and that, for patients with ES secondary to a ventricular septal defect, heart-lung transplantation may offer a survival benefit.24 For patients with ES, we often defer transplantation for many years based on overall risk-benefit considerations. For ES patients, we generally reserve transplantation for those patients who are very symptomatic despite optimal medical management, in whom long-term survival is unlikely, ie, patients in whom likelihood of 2-year survival is less than 50%.Adults with ES must be advised to avoid situations that could exacerbate their pulmonary vascular disease. For example, exercise should be guided by symptoms, with self-limits placed. Avoidance of travel to high altitudes should be advised. In addition, because flight cabins are not usually pressurized to sea level, we recommend the use of supplemental oxygen during air flight to avoid exacerbation of pulmonary hypertension.Pregnancy, oral contraceptives, hormone replacement therapies, and appetite suppressants should be avoided. Pregnancy can be fatal for patients with ES both in the course of delivery and in the postpartum period. During pregnancy, the SVR can fall considerably and lead to increased right-to-left shunting with worsening hypoxemia, which can be dangerous for both the mother and fetus. Similarly, hemorrhage and anesthetic agents may have the same effects on SVR during the peripartum period. Thromboembolic events have also been associated with up to 43% of all maternal deaths in ES.25 The practice at our institution is to firmly advise against pregnancy, as the risk for maternal death is approximately 30% to 50% in the peripartum period.25 In addition, because of the increased risk of thromboembolic events, which may be associated with oral contraceptives and hormone replacement therapies, we advise against oral contraceptive therapies for all of our ES patients and suggest barrier methods or tubal ligation as alternatives.There are several novel therapeutic agents that are currently being evaluated and/or considered for clinical investigation for patients with PAH, alone as well as in combination. These include endothelin-receptor antagonists, prostacyclin analogues, elastase inhibitors, inhaled nitric oxide, phosphodiesterase-5 inhibitors, eg, sildenafil, and angiotensin-converting enzyme inhibitors.Endothelin-1 (ET-1), a very potent vasoconstrictor, is elevated in patients with PPH, and correlates inversely with prognosis.26 Plasma ET-1 levels are also elevated in patients with ES.27 The endothelin-receptor antagonists bosentan and sitaxsentan have been shown to improve exercise capacity, hemodynamics, and WHO functional classification in patients with PPH, PAH associated with collagen vascular disorders, and PAH with associated CHD.28–32 Future prospective studies, which will include a greater number of patients with CHD, will be critical for determining whether this class of drug is also effective for patients with ES.Other novel therapeutic agents: Other novel therapeutic agents, including oral and inhaled prostacyclin analogues, elastase inhibitors, inhaled nitric oxide, phosphodiesterase inhibitors, and angiotensin-converting enzyme inhibitors, are being investigated in patients with PAH and may show promise for the long–term management of ES.While there have recently been many advances in the understanding of the pathobiology and management of adults with ES, there is still no cure for this disease. By furthering our understanding of the disease, we anticipate that more advances will continue for patients with ES, thereby improving the long-term outlook for these patients.