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| REVIEW ARTICLE |
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| Year : 2010 | Volume
: 2
| Issue : 2 | Page : 69-74 |
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Pulmonary arterial hypertension in adults with congenital heart disease: The Eisenmenger syndrome
Antonio Augusto Lopes1, André Cogo Dalmaschio2
1 Department of Pediatric Cardiology and Adult Congenital Heart Disease, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
2 Heart Institute, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
| Date of Web Publication | 16-Aug-2010 |
Correspondence Address:
Antonio Augusto Lopes
Department of Paediatric Cardiology and Adult Congenital Heart Disease - The Heart Institute (InCor) - HC.FMUSP - Av. Dr. Eneas de Carvalho Aguiar, 44 - 05403-900 - Sao Paulo
Brazil
 DOI: 10.4103/0974-6013.68486
 Abstract | | |
Despite the early surgical repair of congenital cardiac defects in most institutions of developed countries, advanced pulmonary vasculopathy associated with unrepaired shunts remains a major problem, particularly in underserved areas of developing nations. The so called Eisenmenger syndrome (reversed right-to-left shunting caused by heightened pulmonary vascular resistance, sometimes above the systemic level) is a multisystemic disorder associated with progressive right cardiac failure and hypoxemia. Management of this disorder is far beyond the simple administration of vasodilators. Rather, in the era of the "new drugs" for treatment of pulmonary hypertension, general therapeutic measures remain central in patient care. These include monitoring of blood viscosity and prevention of hyperviscosity states, prophylaxis against pulmonary and systemic infections and thrombotic events, monitoring of renal function and systemic blood pressure, contraception in females, and management of specific cardiac complications such as myocardial ischemia and arrhythmias. Keywords: Pulmonary hypertension, Eisenmenger syndrome, thrombosis, hypoxemia, blood hyperviscosity
How to cite this article:
Lopes AA, Dalmaschio AC. Pulmonary arterial hypertension in adults with congenital heart disease: The Eisenmenger syndrome. PVRI Review 2010;2:69-74 |
How to cite this URL:
Lopes AA, Dalmaschio AC. Pulmonary arterial hypertension in adults with congenital heart disease: The Eisenmenger syndrome. PVRI Review [serial online] 2010 [cited 2012 Feb 9];2:69-74. Available from: http://www.pvrireview.org/text.asp?2010/2/2/69/68486 |
| Definition and Epidemiology | |  |
After the initial description of a 32-year-old cyanotic patient who died of massive hemoptysis, with postmortem examination showing a ventricular septal defect (1897, Viktor Eisenmenger), in 1958, Paul Wood [Figure 1] coined the term Eisenmenger complex to define the condition of a large ventricular septal defect associated with heightened pulmonary artery pressure and vascular resistance causing bidirectional or reversed (right-to-left) shunting and systemic oxygen desaturation. Subsequently, the term Eisenmenger syndrome has been used to describe any congenital cardiac septal defect or shunt between the great arteries (persistent ductus arteriosus or aortopulmonary window) associated with advanced pulmonary vascular disease and reversed shunting. [1] There has been some debate whether the condition of a cyanotic anomaly (eg., transposition of the great arteries or univentricular hearts) causing severe pulmonary arterial hypertension (PAH) should be referred to as Eisenmenger syndrome.  | Figure 1 : Paul Hamilton Wood (1907-1962), who coined the term "Eisenmenger complex"
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According to the report of the Joint Study on the Natural History of Congenital Heart Defects, [2] approximately 13% of unoperated patients with a nonrestrictive ventricular septal defect develop the Eisenmenger syndrome. More recently, a 5-year survey on adult congenital heart disease in the European Community revealed that the syndrome was present in 1.6% and 11.7% of all adults with an atrial or ventricular septal defect, respectively. [3] Thus, despite the general agreement that patients with congenital cardiac defects should be assigned to operation early in life, the Eisenmenger syndrome is still prevalent even in developed countries.
| Natural History | | |
Compared with idiopathic pulmonary arterial hypertension (IPAH), the natural history of patients with the Eisenmenger syndrome is considerably better, with survival curves showing that more than 40% of the subjects are expected to be alive 25 years following the diagnosis [2],[4] [Figure 2]. This is important while planning the therapeutic strategies, because outcomes must be analyzed on a long-term basis. Variables that have been demonstrated to be associated with poor outcome are syncope, elevated right atrial pressure and right ventricular filling pressure (8mmHg or above), and peripheral (systemic) oxygen saturation < 85%. [4]  | Figure 2 : Survival curves for patients with Eisenmenger syndrome (from diagnosis) compared with idiopathic pulmonary arterial hypertension (PPH). Data correspond to patients not receiving prostacyclin analogs, endothelin receptor antagonists, or phosphodiesterase inhibitors. Unpublished data from the Heart Institute, São Paulo, Brazil
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In our institution, we have observed that heightened circulating levels of von Willebrand factor (vWF:Ag) are associated with decreased life expectancy in these patients [Figure 3]. For unknown reasons, some subjects in very stable conditions have low plasma endothelial dysfunction marker levels. [5],[6]  | Figure 3 : Short-term (1-year) survival in patients with idiopathic pulmonary arterial hypertension (PPH) and the Eisenmenger syndrome (congenital heart disease-associated pulmonary hypertension [CHD-PH]) as a function of the circulating (plasma) levels of von Willebrand factor (vWF:Ag). For any given level of vWF:Ag, the probability of survival is considerably higher for patients with CHD-PH. Reproduced from Ref. 6, with permission
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| Pathophysiology and Pathology | | |
The Eisenmenger syndrome is a multisystemic disorder that includes chronic hypoxemia, erythrocytosis with increased blood viscosity, vascular abnormalities not only in the pulmonary but also in the systemic circulation, and increased risk of thrombotic events. Hemoptysis, which was interpreted for many years as the result of bleeding diathesis and/or rupture of thin-walled (abnormally dilated) pulmonary vessels, is now known to be associated with pulmonary arterial thrombosis and pulmonary infarction (thrombotic diathesis) as well. On the other hand, hypoxemia and blood hyperviscosity may account for a number of systemic abnormalities, including myalgia, subtle neurologic events (headache, dizziness, and visual disturbances), cerebrovascular accidents, and cerebral abscess. [7] Systemic hypertension associated with decreased renal function and uremia is occasionally seen.
Pulmonary vasculopathy that occurs in the Eisenmenger syndrome is not different from IPAH [8] or pulmonary hypertension (PH) associated with congenital cardiac defects in general, [9] except that large-vessel disease is probably more prevalent, particularly in adults, due to the chronic character of the disorder. Small-vessel abnormalities include medial hypertrophy of the pulmonary arteries and intimal fibrocellular proliferation leading to progressive narrowing of the vascular lumen [Figure 4]. Increased elastolytic activity has been described in association with the whole process of cellular migration into the intima and proliferation. [10] Vascular dilatation may be seen, with angiomatoid structures or plexiform lesions (thin-walled lesions with capillary-like proliferation inside). Finally, necrotizing arteritis may be observed, with reactive inflammatory exudate throughout the vascular layers. [11]  | Figure 4 : Vascular lesions that may be found in patients with pulmonary arterial hypertension associated with congenital heart disease. (a) Medial hypertrophy only; (b) medial hypertrophy associated with abnormalities of the internal elastic lamina (arrow) and intimal proliferation leading to a marked reduction of the lumen; (c) medial hypertrophy and intimal fibrocellular proliferation with an excentric residual lumen (thrombotic lesion). (Courtesy, Dr. Vera D. Aiello, Heart Institute, São Paulo, Brazil)
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Large-vessel abnormalities (extrapulmonary and intrapulmonary) are easily detected by chest computed tomography and include enlargement of the proximal pulmonary arteries (which are sometimes aneurismal), mild-to-massive pulmonary arterial thrombosis, and mild-to-extensive mural calcific deposits. [12] In a study of ours, patient age, peripheral oxygen desaturation, and plasma level of D-dimer were associated with increased likelihood of in situ pulmonary arterial thrombosis, but in multivariate analysis, only the age was found to be an independent predictor of this complication. [13] Occasionally, an enlarged pulmonary trunk may cause extrinsic compression of the left main coronary artery leading to myocardial ischemia. [14]
| Clinical Presentation | | |
The typical patient with Eisenmenger syndrome is an adult with chronic cyanosis and progressive exercise intolerance. Symptoms (in general, class II or III, New York Heart Association) tend to be more prominent during the winter, and include breathlessness, palpitations, chest pain, and syncope (which is associated with poor outcome). Myalgia and arthralgia are frequent complaints, as are headaches, dizziness, and transient visual disturbances. On physical examination, central cyanosis with clubbing is evident [Figure 5]. Right ventricular heave and a loud pulmonary component of the second heart sound are typically present. Abdominal tenderness and peripheral edema may be present as well. [1],[7]  | Figure 5 : Central cyanosis and clubbing in an adult with Eisenmenger syndrome
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Occasionally, patients are seen in the emergency room with serious complications, such as cerebral abscess or cerebrovascular accidents, causing neurologic disturbances, bleeding diathesis, rupture of thin-walled pulmonary vessels or lung infarction causing massive hemoptysis, bacterial endocarditis leading to systemic infection, or severe myocardial dysfunction presenting as low systemic output. Less severe complications include epistaxis or gingival bleeding, calcium bilirubinate gallstones, and hyperuricemia associated with gout arthritis. [1],[7]
| Diagnostic Procedures | | |
The tests that are routinely performed in patients with the Eisenmenger syndrome are summarized in [Table 1]. Additional tests that are performed in patients with PAH in general may be considered in particular instances and include pulmonary function tests, ventilation-perfusion lung scintigraphy, blood screening for connective tissue disease, and screening for schistosomiasis, portal hypertension, and HIV infection. | Table 1 : Tests routinely performed in patients with Eisenmenger syndrome
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Either the 6-min walk test or the cardiopulmonary exercise test can be used to assess the physical capacity in these patients. [15],[16] These tests provide useful information on the behavior of arterial oxygen saturation during exercise. Termination of exercise depends largely on the severity of hypoxemia. Because the prognostic value of peak oxygen consumption deserves further scrutiny in cyanotic patients, the measurement of the 6-min walk distance represents the preferred method in practice.
Transthoracic echocardiography may be used not only to determine the intracardiac anatomy, but also to estimate the hemodynamic parameters, such as pulmonary pressures and vascular resistance. [17],[18] Magnetic resonance imaging is useful to determine intracardiac anatomy in patients with inadequate echocardiographic window, and provides additional information or right (and left) ventricular volumes and function. Neither of these tests can be used as a substitute for cardiac catheterization, but they are useful for repeated patient evaluations on a long-term basis. High-resolution computed tomography is particularly useful to determine the existence and extent of pulmonary arterial thrombosis. [12],[13],[19] It can be used in association with the circulating levels of D-dimer to evaluate subjects presenting with breathlessness, worsening of hypoxemia, chest pain, and hemoptysis.
There is no current substitute for cardiac catheterization when accurate analysis of pulmonary hemodynamics is in order (eg, in clinical trials aimed at determining the efficacy of vasodilators). In these instances, direct measurement of pulmonary vascular resistance is mandatory. It should be emphasized that pulmonary artery pressures are not expected to decrease substantially in the course of vasodilator therapy, because increased pulmonary flow may compensate for decreased pulmonary vascular resistance, with no changes in pressures. An association between acute pulmonary vascular response to vasodilators and prognosis has been demonstrated in adults with Eisenmenger syndrome. [20] However, criteria for a positive response to acute vasodilator administration has not been defined in this syndrome. Those adopted for patients with IPAH (eg, a 10 mmHg drop in the mean pulmonary artery pressure with a final value of <40 mmHg) are definitely not appropriate.
Routine laboratory testing is important in patients with Eisenmenger syndrome, and is summarized in [Table 1]. Attention should be given to coagulation abnormalities (either hypo- or hypercoagulable/prothrombotic states) [21],[22],[23] and altered blood viscosity particularly associated with depletion of iron reserves. Iron deficiency, a common finding in these patients, influences erythrocyte deformability, [24] resulting in increased blood viscosity, clinical deterioration, and heightened risk of thrombotic events. Chronic intravascular coagulation may be present in some patients. Frequent monitoring of D-dimer levels, circulating thrombin-antithrombin complexes, and platelet count is therefore recommended.
| General Therapeutic Measures | | |
For many decades before the era of the so-called new drugs for treatment of PAH, patients with Eisenmenger syndrome were managed conventionally. Those who were adequately assisted had a reasonable quality of life and much better life expectancy compared, for example, with subjects with IPAH. Thus, conventional therapeutic measures remain absolutely important in the management of these patients, even in the era of the "new drugs." General therapeutic measures [Table 2] have not been supported by evidence, and are largely based on personal/institutional expertise. There has been a general agreement that the most important principle in the management of patients with Eisenmenger syndrome is "primum non nocere."
Monitoring of blood viscosity and avoidance of critical hyperviscosity states is mandatory. In this way, monitoring and replenishment of iron reserves is considerably more efficacious than repeated phlebotomies. [25] When absolutely necessary to control hyperviscosity-related symptoms (breathlessness, headaches, dizziness, arthralgia, and visual disturbances associated with a hematocrit > 65%), hemodilution is planned to produce mild reductions in the hematocrit level, not to achieve normal levels. In order to avoid significant changes in circulating blood volumes, hemodilution should be planned so that extracted blood is simultaneously replaced by hyperoncotic solutions. Low-molecular weight dextran may be useful in these instances, even in the presence of decreased platelet counts. [26]
In contrast to IPAH, long-term beneficial effects of chronic oral anticoagulation have not been definitely demonstrated. Arguments against the use of anticoagulants are based on the observation of altered coagulation in some of these patients. Arguments in favor of chronic anticoagulation are based on the age-dependent occurrence of in situ pulmonary arterial thrombosis, which becomes massive in some individuals. [12],[13],[27] Furthermore, it is not known whether anticoagulation prevents extension of the thrombotic lesions once large-vessel intrapulmonary thrombosis is detected by computed tomography. Thus, unless clearly contraindicated, it is our policy to keep patients with Eisenmenger syndrome on chronic oral anticoagulant therapy (warfarin) with careful monitoring of the "international normalized ratio" (INR, which is generally maintained between 2.0 and 3.0 in these subjects).
Other measures seem to be equally relevant. Although there has been a debate about the beneficial effects of chronic oxygen administration in adults with Eisenmenger syndrome, [28] it may be useful for relief of symptoms in selected patients presenting with severe hypoxemia, particularly if lung disease is present in association. Prevention and early treatment of infectious diseases are crucial, in particular taking into account the increased risk of serious complications, such as bacterial endocarditis and cerebral abscess. Annual pneumococcal and influenza vaccination is recommended. Because chronic hypoxemia and blood hyperviscosity may lead to progressive impairment or renal function and systemic hypertension, monitoring of these abnormalities is mandatory.
| Targeted Therapies | | |
Protanoids, endothelin-receptor antagonists and phosphodiesterase inhibitors have been used as an attempt to improve hemodynamics and the physical capacity in patients with Eisenmenger syndrome. Prostacyclin analogs (intravenous administration) have been shown to improve the functional capacity and pulmonary hemodynamics in patients with PH associated with congenital heart disease. [29] Bosentan (oral administration) is probably the most extensively used drug in intention-to-treat open-label studies. [30],[31],[32] A recent randomized placebo-controlled study has become available. [33] Sildenafil (oral administration) has been successfully used in patients with PAH, including subjects with congenital heart disease, [34] but further studies are required to demonstrate its benefits specifically in the Eisenmenger syndrome.
It must be emphasized that treatments with drugs capable of inducing pulmonary vasodilatation and/or improving vascular remodeling is totally palliative in these patients. In contrast to young patients (infants and young children) who might theoretically benefit from a combination of drug therapy (to reduce pulmonary vascular resistance) and surgical procedures planned to limit the increase in pulmonary flow (partial or total closure of septal defects, pulmonary arterial banding), patients with Eisenmenger syndrome who respond favorably to drug therapy are expected to have a modest decrease in pulmonary vascular resistance, not sufficiently impressive to allow for correction of the cardiac defects. Therefore, in these patients, only short- to mid-term improvement of hemodynamics, peripheral oxygen saturation, and physical capacity is expected to occur as a result of successful vasodilator therapy. There is no evidence that such effects can be sustained on a long-term basis. Furthermore, it is not known whether increased flow at sites of drug-induced vasodilatation could provoke further endothelial damage and vascular remodeling. Thus, the long-term effects of the "new drugs" on patient's quality of life and survival remain to be demonstrated. Increased time to lung or heart-lung transplantation would theoretically represent a relevant benefit. But this remains to be demonstrated as well.
| Special Situations - Pregnancy | | |
In view of the considerable risk of serious maternal and fetal complications, pregnancy is strongly discouraged in women with Eisenmenger syndrome. More than that, termination of pregnancy is usually recommended in these instances. There have been reports of a >25% maternal mortality in relation to pregnancy and ~20% prevalence of cardiac abnormalities in the offspring. [35] On the other hand, there are restrictions for the use of hormonal contraceptives in view of the potential risk of thromboembolic complications. [36] Contraception protocols that involve progesterone-only pills or devices may be useful, although controlled studies are needed to evaluate the risk/benefit ratios with their use. Despite these risks and recommendations, some women decide to carry on with their pregnancy. In these instances, hospitalization from the end of the second trimester to delivery, the use of heparin (20,000-40,000 units per day) and supplemental oxygen during the third trimester, and cesarean section may be of help to decrease mortality. [37]
| Summary | | |
The Eisenmenger syndrome is a multisystemic disorder that affects patients at all ages. Although its prevalence tends to be higher in underserved areas/countries, many patients have now been diagnosed and treated in developed countries. Correction of congenital cardiac shunts in the presence of advanced pulmonary vascular disease involves unacceptable risk of poor outcomes and therefore, should be strongly discouraged. Once adequately diagnosed and treated, patients with Eisenmenger syndrome have survival curves considerably better than those with IPAH or PH associated with connective tissue disease. With the development of the so-called new drugs for treatment of PAH, namely prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase inhibitors, substantial short- and mid-term improvements in terms of physical capacity and quality of life have been reported. Until results of further studies become available for a better understanding of the long-term benefits of these treatments, general therapeutic measures remain important in the management of these patients.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]
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