Pulmonary Arterial H y p e r t e n s i o n As s o c i a t e d with Congenital Heart Disease Usha Krishnan, MD, Erika B. Rosenzweig, MD* KEYWORDS Pulmonary arterial hypertension Congenital heart disease Eisenmenger syndrome Operability Fontan
KEY POINTS Pulmonary arterial hypertension (PAH) is a frequent complication of congenital heart disease (CHD), most commonly occurring with systemic-to-pulmonary shunt lesions. Given similar histopathologic changes, clinical presentation, and response to targeted therapy, PAH associated with CHD is classified with other forms of PAH in World Health Organization group 1. Prognosis varies depending on the type of congenital heart defect, and the timing of the manifestation of PAH. PAH associated with univentricular heart (both before and after total cavo-pulmonary connection), forms a unique and challenging subgroup of APAH-CHD, with different diagnostic and prognostic criteria and therapeutic indications.
In the modern era, with increasing survival of patients with congenital heart disease (CHD), pulmonary arterial hypertension (PAH) associated with CHD (APAH-CHD) is more commonly encountered.1,2 This increased prevalence has been seen despite significant advances in early diagnosis and surgical correction of patients with structural heart disease. PAH is the cause of significant morbidity and mortality in these patients and comes in many forms. In comparison with patients with idiopathic PAH (IPAH), the pathophysiology of PAH with CHD varies with the underlying anatomy of the defect, presence and size of shunt, and status of the right ventricle (RV). In patients with
unoperated large systemic to pulmonary shunts and subsequent development of classic Eisenmenger physiology with shunt reversal, PAH results from pulmonary vascular remodeling due to initial increased pulmonary blood flow (PBF) and shear stress.3 Despite differences in pathophysiologic triggers, the histopathologic and pathobiologic changes at the level of the pulmonary arterioles in APAH-CHD are remarkably similar to IPAH. Thus these conditions have been grouped together into World Health Organization (WHO) group 1 PAH according to the Dana point classification system.4 Further, there are similarities as well as differences in the clinical presentation, disease progression, and management strategies
Disclosures: Dr Erika B. Rosenzweig has received honoraria from Actelion, Gilead, and United Therapeutics for advice at scientific advisory board meetings. Dr Rosenzweig’s institution also receives research grant support for clinical trials from Actelion, Bayer, Gilead, GSK, Eli Lilly, and United Therapeutics. Dr Usha Krishnan has received honoraria for CME balanced lectures from Actelion and Gilead. Columbia University Medical Center, Pulmonary Hypertension Center, Division of Pediatric Cardiology, 3959 Broadway, CH-2N, New York, NY 10032, USA * Corresponding author. E-mail address: [email protected] Clin Chest Med 34 (2013) 707–717 http://dx.doi.org/10.1016/j.ccm.2013.08.011 0272-5231/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
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Krishnan & Rosenzweig between APAH-CHD and other forms of group 1 PAH. With availability of targeted therapies for PAH, there is hope for improved hemodynamics, exercise capacity, quality of life, and possibly survival in these patients.
EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF APAH-CHD Data from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) registry and the French registry estimate the prevalence of APAH-CHD to be between 10% and 11% of all patients with pulmonary hypertension.5,6 This number is likely to continue to grow as the number of patients with CHD surviving to adulthood rises. In the pediatric age group, CHD forms a much larger proportion of patients with PAH.7 PAH is a type of PH characterized by having mean pulmonary artery pressure greater than or equal to 25 mmHg at rest, with mean pulmonary artery wedge pressure (PAWP) 15 mm Hg or less. In patients with CHD, it is important to differentiate between PAH with low pulmonary vascular resistance (PVR) versus high PVR, which implies vasoconstriction and changes at the arteriolar level. For example, patients with large post tricuspid shunts can have elevated pulmonary arterial pressures (PAPs) without elevation of PVR, due to increased PBF from large systemic to pulmonary shunts. However, with prolonged exposure of the pulmonary circulation to increased flow, vasoconstriction, intimal proliferation, in situ thrombosis, impaired apoptosis, vascular remodeling, and inflammation ensue, all of which contribute to increasing PVR and irreversible vascular disease.8 These histopathologic changes are very similar to those seen in the lungs of patients with IPAH. However, there are important differences in the clinical presentation, physiology, and outcome of the 2 conditions. Despite similar changes at the level of the lung microvasculature and the endothelium, the effect of these changes on the RV are different in APAH-CHD versus IPAH. Despite hypertrophy and dilatation, the RV systolic function can remain normal for decades in the patient with classic Eisenmenger syndrome (ES). This is due to the ability of the RV to unload itself with a right to left shunt, reducing the pressure overload on the RV at the cost of cyanosis. Another hypothesis proposed in these patients to account for the relatively preserved RV function is that these RVs are subjected to systemic pressures from fetal life, and have never undergone the postnatal regression that normally occurs in other forms of PAH. This RV phenotype
may be better able to work against higher resistances for a longer time.9
ANATOMIC AND PHYSIOLOGIC CLASSIFICATION Even among patients with APAH-CHD, there are several clinical subtypes with significant differences in clinical manifestations and outcome, leading to investigators further classifying this group. Simonneau and colleagues4 in 2009 proposed an important classification to better describe the anatomy and physiology of patients with APAHCHD. The classification describes 5 anatomic features, including (1) defect type (including simple or complex defects), (2) defect size hemodynamically speaking (by amount of shunting) and anatomic size (by dimensions), (3) direction of shunt, (4) associated cardiac or extracardiac anomalies, and (5) repair status (Box 1). Unrestrictive post tricuspid shunts, for example, large ventricular septal defects (VSD) and aortopulmonary shunts begin developing pulmonary vascular disease in early childhood as compared with pretricuspid defects, such as atrial septal defects (ASD). Directionality of the shunt can be determined by echocardiography, as well as clinically by oximetry at rest and during exercise. In patients with a patent ductus arteriosus (PDA), preductal and postductal saturations10 should be checked to look for right to left shunting at rest and with exertion. The repair status of the defect is also important, as patients with severe residual PAH after closure of shunts may have more rapid progression of disease and worse outcome, similar to IPAH, than those with unrepaired shunts and ES physiology.
CLINICAL CLASSIFICATION Simonneau and colleagues4 also proposed a clinical classification of APAH-CHD, which best describes their physiologic and clinical subtype. These 4 physiologic subtypes of patients with APAH-CHD, are described in Box 2: Subgroup 1, patients with classic ES (inoperable with reversal of shunt) Subgroup 2, patients with large systemic to pulmonary shunts but low PVR that are operable Subgroup 3, patients with severe PAH in the setting of small restrictive CHD with physiology and course similar to IPAH patients; these patients are at increased risk for more rapidly progressive RV failure and have worse
PAH and Congenital Heart Disease
Box 1 Anatomic classification of congenital systemicto-pulmonary shunts
Box 2 Clinical classification of congenital systemic-topulmonary shunts associated with PAH
1. 1.1. 1.1.1. 1.1.1.1. 1.1.1.2. 1.1.1.3. 1.1.2.
Eisenmenger syndrome
1.2 1.2.1. 1.2.2. 1.3
1.4 1.4.1. 1.4.2. 1.4.3.
1.4.4.
1.4.5. 2. 2.1.
2.1.1. 2.1.2. 2.2. 2.2.1. 2.2.2. 3. 3.1 3.2 3.3 4. 5. 5.1. 5.2. 5.3.
Type Simple pretricuspid shunts Atrial septal defect (ASD) Ostium secundum Sinus venosus Ostium primum Total or partial unobstructed anomalous pulmonary venous return Simple post-tricuspid shunts Ventricular septal defect (VSD) Patent ductus arteriosus (PDA) Combined shunts (describe combination and predominant defect) Complex congenital heart disease Complete atrioventricular septal defect Truncus arteriosus Single-ventricle physiology with unobstructed pulmonary blood flow Transposition of the great arteries with VSD (without pulmonary stenosis) and/or PDA Other Dimension (specify for each defect if more than 1) Hemodynamic (specify ratio of pulmonary-to-systemic blood flow) Restrictive (pressure gradient across the defect) Nonrestrictive Anatomic Small to moderate (ASD 2 cm and VSD 1 cm) Large (ASD >2 cm and VSD >1 cm) Direction of shunt Predominantly systemic-topulmonary Predominantly pulmonary-tosystemic Bidirectional Associated cardiac and extracardiac abnormalities Repair status Unoperated Palliated (specify type of operation(s), age at surgery) Repaired (specify type of operation(s), age at surgery)
From Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54(Suppl 1):S43–54; with permission.
PAH with moderate to large defects
PAH with small defects
PAH following corrective cardiac surgery
Patients with unrepaired systemicto-pulmonary shunts resulting from large, nonrestrictive defects leading to a severe, progressive increase in PVR, bidirectional shunting, and ultimately reversed shunting with central cyanosis PVR is mildly to moderately increased, systemic-topulmonary shunt is still present, and no cyanosis is present at rest Smaller defects generally include VSD 1 cm and ASD 2 cm, and clinical picture is similar to IPAH CHD has been corrected, but PAH is present either immediately after surgery or recurs several months or years after surgery in the absence of significant residual shunts
Abbreviations: ASD, atrial septal defect; CHD, congenital heart disease; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; PVR, pulmonary vascular resistance; VSD, ventricular septal defect. From Simonneau G, Robbins IM, Beghetti M, et al. Updated Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54(Suppl 1):S43–54; with permission.
outcomes than patients with ES, as there is no pop-off mechanism to unload the RV Subgroup 4, postoperative residual or recurrent PAH Some patients develop PAH months or even years following surgery, despite shunt closure being performed at an appropriate age. Although genetic factors may play a role in their predisposition to develop PAH, it is not completely understood why some patients develop PAH even with timely repair of a systemic to pulmonary shunt. Patients with postoperative PAH also act
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Krishnan & Rosenzweig physiologically like IPAH, and need to be treated more aggressively, with strategies similar to those used for IPAH. Manes and colleagues10 analyzed data from 192 patients with APAH-CHD collected over 13 years, and compared the outcomes of different subtypes of APAH-CHD with patients with IPAH. The investigators demonstrated that patients with ES had the highest baseline PVR and lowest exercise capacity. However, they also found a 20-year Kaplan-Meier survival estimate of 87% for ES compared with 36% in postoperative APAH-CHD. Other studies have also shown a favorable prognosis for patients with APAH-CHD as compared with IPAH.9,11,12 However, in 2010, when the long-term outcomes data from the REVEAL study were analyzed, survival in patients with APAH-CHD was not significantly different from that in patients with IPAH.13 This is probably because this study included all 4 subgroups of patients with APAH-CHD and not just the patients with type 1 ES, who appear to have a survival advantage over IPAH and postoperative APAHCHD.10 Management of patients within the first 2 categories, those with Eisenmenger physiology and those with PAH in the setting of unrepaired moderate to large defects, poses added challenges, and is the focus of the remainder of this article. Management of groups 3 and 4 is similar to the management of patients with IPAH.
PAH ASSOCIATED WITH UNRESTRICTIVE SYSTEMIC TO PULMONARY SHUNTS The clinical presentation of APAH-CHD depends on the status of pulmonary vascular disease at the time of evaluation. In patients with large shunts and normal PVR, such as the infant with a large, nonrestrictive VSD, increased PBF, and congestive heart failure, the presentation is usually of failure to thrive, feeding intolerance, resting tachypnea, and recurrent respiratory infections. In these patients, surgical therapy after medical stabilization is the treatment of choice. Even within this group, in about 2% of children with large systemic to pulmonary shunts present, postoperative PAH occurs, with approximately 0.75% suffering PH crises.14 In these patients, mortality remains relatively high at 20% to 30%.14–17 Children at risk for postoperative PAH crises are often those with Down syndrome, complex CHD (atrioventricular canal defects, aortopulmonary window, transposition of great arteries, and truncus arteriosus), and children with very reactive PAH with PH crises in the preoperative period.15 In patients with large systemic to pulmonary shunts presenting at an older age, careful
evaluation to determine operability is critical before repair. Patients with APAH-CHD (see Box 2) with modestly elevated PVR and moderate systemic to pulmonary shunts (type 2) are also quite challenging to manage.18 Determining whether the patient is operable, and if the patient would benefit with pretreatment with targeted therapies is essential, although there are no evidence-based guidelines available. Closing a defect should not be performed just because it can be, but rather only when the PAH is likely to improve after surgical intervention. This is an important point, particularly now that we have data that show that patients with postoperative APAH-CHD fare worse than other forms of APAH-CHD. Cardiac catheterization and acute vasodilator testing remain important tools to help determine safe operability in these patients. Although no validated criteria exist for predicting long-term postsurgical morbidity and mortality, a complete set of hemodynamics should be obtained; vasodilator testing and temporary balloon occlusion of the defect may also be helpful. Obtaining resting room air oxygen saturations and then oxygen saturation following exertion can be helpful in the assessment of operability. For a patient with resting cyanosis or even cyanosis with exertion, closing the defect can lead to worsening right heart failure by removing the pressure/volume “pop-off” that the defect affords the right ventricle. Other important elements of the history include age at diagnosis, current age, and type and size of CHD. The importance of the type of CHD has been previously discussed, and, in general, the earlier a shunt lesion is diagnosed, the more likely the patient is operable. A history suggestive of initial congestive heart failure, including recurrent respiratory infection and effort intolerance, which improves over time to a “honeymoon period” of symptomatic relief, is suspicious of the development of irreversible pulmonary vascular disease with less net left to right shunting. In this situation, exercise testing may reveal latent cyanosis. Elevated hemoglobin in an iron replete patient, suggesting erythrocytosis in response to hypoxia, may also indicate intermittent right to left shunting through the course of the day.
INTERPRETATION OF HEMODYNAMIC DATA Indices of right heart function, including right atrial pressure and cardiac index, are important determinants of prognosis in IPAH.15 In patients with APAH-CHD, PVR also becomes an important tool for the assessment of the patient. It is essential to understand that PAH in patients with large systemic to pulmonary shunts can be due to an
PAH and Congenital Heart Disease increase in PBF or due to an increase in the PVR. In patients with a large unrestrictive VSD or PDA, PAP will be at systemic levels regardless of the PVR because of the increase in PBF (PBF [Qp]:systemic blood flow [Qs]). In contrast, elevation in the PVR is determined by the extent of pulmonary vascular obstructive disease (PVD). Therefore, in patients with APAH-CHD, calculation of the PVR is clinically important as well. In a patient with a large shunt and normal PVR index (PVRi) less than 3 U M2, complete repair of the defect is usually not associated with residual PAH. However, when there is elevation of PVR above 6 U M2, completely repairing the defect can be dangerous and associated with residual PAH and postoperative PH crises and RV strain. During the hemodynamic evaluation of a systemic-to-pulmonary shunt, baseline room air hemodynamics should include 3 complete oxygen saturation runs and pressure measurements in the superior vena cava, right atrium (RA), RV, pulmonary artery (PA), and pulmonary capillary wedge pressures (PCWP). Once baseline data are collected, if there is no elevation of PAWP and PVRi is greater than 3 U M2, acute vasodilator testing should be performed and another full assessment should be performed. Data should be obtained in the absence of respiratory or metabolic acidosis, anemia, or agitation. Nevertheless, the issue of determining operability is not straightforward and has been highlighted in several recent articles.19–21 Lopes and O’Leary21 proposed the following hemodynamic criteria for operability, based on existing literature and surveying centers of excellence with experience in the treatment of pulmonary hypertensive patients: baseline PVRi less than 6 WU M2 and PVR-SVR ratio less than 0.3. Acute vasodilator testing (AVT) was suggested if PVR at baseline was 6 to 9 WU M2 with a PVR-SVR ratio of 0.3 to 0.5. In these patients, a favorable outcome is considered likely if with AVT, the following criteria are met: (1) a decrease of PVRi by greater than 20%, (2) a decrease in PVR-SVR ratio by 20%, (3) a final PVR less than 6 WU M2, and (4) a final PVR-SVR ratio less than 0.3. Other centers have reported higher baseline PVRi values for operability PVRi less than or equal to 7 to 8 WU M2 and PVR-SVR ratios of less than or equal to 0.4.22,23 None of these studies report long-term outcomes following closure of the defects, and the question of the benefits of pretreating with targeted PAH therapies before surgical repair remains unanswered. Cardiac catheterization alone, however, is usually not sufficient to determine operability. The hemodynamic findings must be taken in the context of the medical history, physical examination, and
results of all invasive and noninvasive testing. For example, in a case of borderline PVR at rest in the catheterization laboratory, but with significant exertional cyanosis, shunt repair may be more harmful than beneficial. In patients with “borderline” hemodynamics (eg, PVRi 3 to 6 U M2), there may be an evolving role for a combined medical-surgical approach. Although this has not been proven to provide long-term benefit, there have been anecdotal cases, including at our own institution, of being able to partially repair after using targeted PAH therapy in borderline cases (Fig. 1). It may be reasonable to treat with targeted PAH therapies for a period of months, and serially reevaluate by catheterization to determine operability or partial operability with intentional creation of a small residual defect as a “pop-off.”18–20 In rare borderline patients, medical therapy may drop the PVR enough to increase the left to right shunt to such an extent that there is significantly elevated PBF and the patient develops signs and symptoms of high-output failure.20 As a result, surgical shunt closure should be expeditiously performed to protect the pulmonary vasculature from high flowrelated damage. Surgery on a patient with borderline PAH should be undertaken after careful consideration of all these factors and there should be a multidisciplinary team approach involving the cardiologist, surgeon, intensivists, anesthesiologists, and the postoperative intensive care unit team. Care should be taken to anticipate and avoid PA pressure swings during induction of anesthesia and during recovery. Circulating vasoactive factors from blood products (like platelets) are known to precipitate PAH crises and should be avoided if possible. In the postoperative period, use of pulmonary vasodilators, including inhaled nitric oxide (iNO) and adequate oxygenation, as well as avoidance of respiratory acidosis, is essential. Some patients may require sedation (and/or paralysis) and mechanical ventilation for several days if they have labile PH in the postoperative period. The use of sildenafil while weaning iNO has been found to be effective in preventing rebound PH in some cases.24
EISENMENGER SYNDROME The term “Eisenmenger syndrome” (ES) was coined by Paul Hamilton Wood in 1958 to define the condition of increased PAP and PVR in relation to a VSD with resultant shunt reversal and cyanosis. Currently, the term Eisenmenger physiology has been expanded to include any reversed shunt secondary to elevated PVR, including shunts associated with complex
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Fig. 1. APAH-CHD (ASD) clinical management algorithm: individualized case approach. ASD, atrial septal defect; AVT, acute vasodilator testing; PVR:SVR ratio, ratio of pulmonary vascular resistance to systemic vascular resistance; PVRI, pulmonary vascular resistance indexed to body surface area; TBO, temporary balloon occlusion. (From Rosenzweig EB, Barst RJ. Congenital heart disease and pulmonary hypertension: pharmacology and feasibility of late surgery. Prog Cardiovasc Dis 2012;55(2):128–33; with permission.)
CHD.25 With timely CHD diagnosis and cardiac surgery, especially during infancy, survival of patients into adulthood is commonplace, and the worldwide incidence of ES has declined by 50%.26,27 However, ES still remains a significant problem in the developing world, where patients with large shunts are unable to undergo repair before the development of PVD. The worldwide prevalence of PAH in adults with CHD has recently been estimated at between 1.6 and 12.5 million, with 25% to 50% presenting with ES.28 Although life expectancy is reduced in ES, it is significantly better than IPAH, with many patients with ES surviving into their third and fourth decades, and even some into their seventh decade.26,27 More than 40% of subjects are expected to be alive 25 years after diagnosis. Fig. 2 shows the Kaplan-Meier curves of life expectancy in simple versus complex lesions leading to ES.29 Patients with complex lesions have a much worse prognosis than those with simple shunts. However, with advances in targeted therapies, the outlook for patients with ES may improve, as a recent study predicted Kaplan-Meier survival estimate at 20 years of 87% in patients with ES.10 The presentation and clinical course of ES are a result of chronic hypoxia and are different from those of IPAH. Patients with ES often have
objective evidence of significant effort intolerance, but may not perceive their limitation because of the chronicity of their disease. Their symptoms and complications are secondary to the cyanosis, erythrocytosis, and end-organ damage. On physical examination, central cyanosis with clubbing
Fig. 2. Survival prospects of patients with Eisenmenger physiology when compared with an ageand gender-matched healthy population showing reduced life expectancy in patients with ES. y, Predicted survival is based on the life tables for UK and Wales (2001–2003 interim life tables) published by the Government Actuary’s Department. *, Comparison between Eisenmenger patients with simple and complex lesions. Patients with complex lesions had a significantly worse outcome compared with those with simple lesions.
PAH and Congenital Heart Disease may be present, RV heave and a prominent second heart sound are often present, and hepatomegaly and peripheral edema may be appreciated in more advanced cases. Patients may also present with serious complications, such as cerebral abscess or stroke, pulmonary arterial thrombosis, massive hemoptysis due to rupture of thin-walled pulmonary vessels, bacterial endocarditis, or severe myocardial dysfunction with low cardiac output.
MANAGEMENT STRATEGIES FOR ES In the past, treatment options for patients with ES had been limited to palliative therapies and heartlung transplantation or lung transplantation with repair of the CHD. However, over the past decade, there has been growing experience using both conventional and targeted PAH therapies in patients with ES. Commonly used conventional therapies include digoxin, diuretics, anticoagulation, and antiarrhythmics, although none of these have been shown to improve survival in ES. Anticoagulation in patients with ES remains controversial because of increased risks of pulmonary artery thrombosis, as well as hemoptysis, stroke, and hemorrhage. Although the benefit of anticoagulation in patients with IPAH has been demonstrated, no such data exist for patients with ES, and, given the potential complications, the decision to anticoagulate should be made carefully on an individual case basis. Oxygen is often used long term in patients with ES, and although it may be associated with improvement in subjective status, no survival benefit has been seen. Maternal mortality in patients with ES is reported at approximately 50%, with death usually occurring during delivery or the first postpartum week due to hypervolemia, thromboembolism, or preeclampsia. In addition, spontaneous abortion rates are quite high, and for infants carried to term, there are high rates of intrauterine growth retardation and perinatal mortality.29–31 As a result, pregnancy is contraindicated in ES.
TARGETED THERAPIES FOR ES There are 3 main classes of targeted PAH therapies initially used in patients with group 1 PAH, and currently, all have been used in the treatment of patients with ES. These include prostanoids, endothelin receptor antagonists (ERAs), and phosphodiesterase-5 (PDE5) inhibitors. The aim of targeted therapies in patients with ES is to improve exercise tolerance by improving PBF, hypoxemia, physical capacity, and, ultimately, survival.
Prostanoids The use of intravenous epoprostenol in ES was first described by Rosenzweig and colleagues32 in 1999, with subjects showing improvements in functional capacity, hemodynamics, and survival. Because epoprostenol is chemically unstable at neutral pH/room temperature, and has a short half-life (1–2 minutes), a continuous intravenous delivery system with cold packs is needed to maintain stability. An indwelling central venous line is necessary, with associated complications, including thrombosis and line occlusion, local and systemic infection, and catheter breakage. The risk of thromboembolism is of particular concern in patients with ES with right to left shunts. In addition, pump malfunction may rarely lead to administration of a sudden bolus of epoprostenol (leading to systemic hypotension) or interruption of the medication, which can cause severe rebound PAH. Therefore, a search for alternate routes of drug delivery has led to the approval of inhaled (iloprost, treprostinil), subcutaneous (treprostinil), and more stable and longer-acting intravenous prostacyclin analogues (treprostinil, veletri). Treprostinil sodium is a prostacyclin analogue with a neutral pH, longer half-life, which is stable at room temperature, and shares the same pharmacologic actions as epoprostenol with potential advantages by being able to deliver the agent via inhalation or subcutaneous infusion, thus eliminating the risk of thromboembolic events in patients with ES.33
ERAs Endothelin (ET)-1 is one of the most potent vasoconstrictors implicated in the pathobiology of PAH and plasma ET-1 levels are increased in patients with IPAH (and other forms of PAH) and correlate inversely with prognosis. The first randomized, double-blinded, placebo-controlled study in patients with ES was the Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) trial investigating the efficacy and safety of the dual ERA bosentan in patients with ES.34,35 During the 16-week study, bosentan significantly reduced PVR, and improved PAP and exercise capacity compared with placebo without worsening oxygenation, and longer-term data from the follow-up portion of the study demonstrated continued improvements in exercise capacity over an additional 24 weeks.35 The study also demonstrated a worsening of PVR in the placebo group, which underscores the progressive nature of untreated ES. Risks associated with ERAs include acute hepatotoxicity (bosentan), teratogenicity, and possibly male
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Krishnan & Rosenzweig infertility. The selective ERA ambrisentan may offer potential advantages over bosentan, given its selectivity for the ET-A receptor, which demonstrates vasoconstrictor effects, although this remains controversial. Ambrisentan, which can be administered once a day, was also found to be efficacious in a series of patients with ES with an acceptable safety profile.36
PDE5 Inhibitors PDE5 inhibitors prevent the inactivation of cyclic guanosine monophosphate (GMP), thereby raising cyclic GMP levels. Oral sildenafil is the most widely used of the PDE5 inhibitors in the treatment of PAH, and has been used in children with APAH-CHD, with benefits on exercise capacity and hemodynamics.37 In a recent prospective, open-label, multicenter study, using sildenafil, patients with ES demonstrated an acceptable safety profile and improved exercise capacity, oxygen saturation, and hemodynamics after 12 months of therapy.38 A recent randomized, placebo-controlled, double-blinded crossover study using tadalafil in patients with ES also demonstrated safety and short-term improvements in exercise capacity, functional class, oxygen saturation, and hemodynamics after 6 weeks of therapy.39
Lung and Heart Lung Transplantation Currently, the overall 1-year, 5-year, and 10-year survival for lung transplantation for patients with PAH is 64%, 44%, and 20%, respectively.40–42 For patients with untreated ES, the 5-year and 25-year survival is greater than 80% and 40%, respectively as opposed to following lung transplantation (52% and 39%).40–42 Thus, lung transplantation should be reserved for patients with WHO functional class IV symptoms with an estimated likelihood of survival of less than 50% at 5 years. Although lung and heart/lung transplantation are imperfect therapies for pulmonary arterial hypertension, when offered to an appropriately selected population, transplantation may improve survival with an improved quality of life. The use of extracorporeal membrane oxygenation as a bridge to recovery (in acutely decompensated patients), as well as a bridge to transplantation, may also be a viable option in selected patients.42
PULMONARY HYPERTENSION IN THE UNIVENTRICULAR HEART: THE FAILING FONTAN The Fontan (total cavopulmonary connection) circulation, which is surgically created for
hypoplastic left heart syndrome, lacks a pumping subpulmonary ventricle, and is dependent on the central venous pressure to perfuse the pulmonary circulation. Thus, changes in the PVR can have a tremendous impact on forward flow in this circulation. For patients with a single ventricle, the hemodynamic criteria used for shunt closure do not apply for predicting operability. Pre-Fontan PVRi should be normal in these patients, to sustain the cavopulmonary circulation (ie,
KEY POINTS Pulmonary arterial hypertension (PAH) is a frequent complication of congenital heart disease (CHD), most commonly occurring with systemic-to-pulmonary shunt lesions. Given similar histopathologic changes, clinical presentation, and response to targeted therapy, PAH associated with CHD is classified with other forms of PAH in World Health Organization group 1. Prognosis varies depending on the type of congenital heart defect, and the timing of the manifestation of PAH. PAH associated with univentricular heart (both before and after total cavo-pulmonary connection), forms a unique and challenging subgroup of APAH-CHD, with different diagnostic and prognostic criteria and therapeutic indications.
In the modern era, with increasing survival of patients with congenital heart disease (CHD), pulmonary arterial hypertension (PAH) associated with CHD (APAH-CHD) is more commonly encountered.1,2 This increased prevalence has been seen despite significant advances in early diagnosis and surgical correction of patients with structural heart disease. PAH is the cause of significant morbidity and mortality in these patients and comes in many forms. In comparison with patients with idiopathic PAH (IPAH), the pathophysiology of PAH with CHD varies with the underlying anatomy of the defect, presence and size of shunt, and status of the right ventricle (RV). In patients with
unoperated large systemic to pulmonary shunts and subsequent development of classic Eisenmenger physiology with shunt reversal, PAH results from pulmonary vascular remodeling due to initial increased pulmonary blood flow (PBF) and shear stress.3 Despite differences in pathophysiologic triggers, the histopathologic and pathobiologic changes at the level of the pulmonary arterioles in APAH-CHD are remarkably similar to IPAH. Thus these conditions have been grouped together into World Health Organization (WHO) group 1 PAH according to the Dana point classification system.4 Further, there are similarities as well as differences in the clinical presentation, disease progression, and management strategies
Disclosures: Dr Erika B. Rosenzweig has received honoraria from Actelion, Gilead, and United Therapeutics for advice at scientific advisory board meetings. Dr Rosenzweig’s institution also receives research grant support for clinical trials from Actelion, Bayer, Gilead, GSK, Eli Lilly, and United Therapeutics. Dr Usha Krishnan has received honoraria for CME balanced lectures from Actelion and Gilead. Columbia University Medical Center, Pulmonary Hypertension Center, Division of Pediatric Cardiology, 3959 Broadway, CH-2N, New York, NY 10032, USA * Corresponding author. E-mail address: [email protected] Clin Chest Med 34 (2013) 707–717 http://dx.doi.org/10.1016/j.ccm.2013.08.011 0272-5231/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
chestmed.theclinics.com
INTRODUCTION
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Krishnan & Rosenzweig between APAH-CHD and other forms of group 1 PAH. With availability of targeted therapies for PAH, there is hope for improved hemodynamics, exercise capacity, quality of life, and possibly survival in these patients.
EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF APAH-CHD Data from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) registry and the French registry estimate the prevalence of APAH-CHD to be between 10% and 11% of all patients with pulmonary hypertension.5,6 This number is likely to continue to grow as the number of patients with CHD surviving to adulthood rises. In the pediatric age group, CHD forms a much larger proportion of patients with PAH.7 PAH is a type of PH characterized by having mean pulmonary artery pressure greater than or equal to 25 mmHg at rest, with mean pulmonary artery wedge pressure (PAWP) 15 mm Hg or less. In patients with CHD, it is important to differentiate between PAH with low pulmonary vascular resistance (PVR) versus high PVR, which implies vasoconstriction and changes at the arteriolar level. For example, patients with large post tricuspid shunts can have elevated pulmonary arterial pressures (PAPs) without elevation of PVR, due to increased PBF from large systemic to pulmonary shunts. However, with prolonged exposure of the pulmonary circulation to increased flow, vasoconstriction, intimal proliferation, in situ thrombosis, impaired apoptosis, vascular remodeling, and inflammation ensue, all of which contribute to increasing PVR and irreversible vascular disease.8 These histopathologic changes are very similar to those seen in the lungs of patients with IPAH. However, there are important differences in the clinical presentation, physiology, and outcome of the 2 conditions. Despite similar changes at the level of the lung microvasculature and the endothelium, the effect of these changes on the RV are different in APAH-CHD versus IPAH. Despite hypertrophy and dilatation, the RV systolic function can remain normal for decades in the patient with classic Eisenmenger syndrome (ES). This is due to the ability of the RV to unload itself with a right to left shunt, reducing the pressure overload on the RV at the cost of cyanosis. Another hypothesis proposed in these patients to account for the relatively preserved RV function is that these RVs are subjected to systemic pressures from fetal life, and have never undergone the postnatal regression that normally occurs in other forms of PAH. This RV phenotype
may be better able to work against higher resistances for a longer time.9
ANATOMIC AND PHYSIOLOGIC CLASSIFICATION Even among patients with APAH-CHD, there are several clinical subtypes with significant differences in clinical manifestations and outcome, leading to investigators further classifying this group. Simonneau and colleagues4 in 2009 proposed an important classification to better describe the anatomy and physiology of patients with APAHCHD. The classification describes 5 anatomic features, including (1) defect type (including simple or complex defects), (2) defect size hemodynamically speaking (by amount of shunting) and anatomic size (by dimensions), (3) direction of shunt, (4) associated cardiac or extracardiac anomalies, and (5) repair status (Box 1). Unrestrictive post tricuspid shunts, for example, large ventricular septal defects (VSD) and aortopulmonary shunts begin developing pulmonary vascular disease in early childhood as compared with pretricuspid defects, such as atrial septal defects (ASD). Directionality of the shunt can be determined by echocardiography, as well as clinically by oximetry at rest and during exercise. In patients with a patent ductus arteriosus (PDA), preductal and postductal saturations10 should be checked to look for right to left shunting at rest and with exertion. The repair status of the defect is also important, as patients with severe residual PAH after closure of shunts may have more rapid progression of disease and worse outcome, similar to IPAH, than those with unrepaired shunts and ES physiology.
CLINICAL CLASSIFICATION Simonneau and colleagues4 also proposed a clinical classification of APAH-CHD, which best describes their physiologic and clinical subtype. These 4 physiologic subtypes of patients with APAH-CHD, are described in Box 2: Subgroup 1, patients with classic ES (inoperable with reversal of shunt) Subgroup 2, patients with large systemic to pulmonary shunts but low PVR that are operable Subgroup 3, patients with severe PAH in the setting of small restrictive CHD with physiology and course similar to IPAH patients; these patients are at increased risk for more rapidly progressive RV failure and have worse
PAH and Congenital Heart Disease
Box 1 Anatomic classification of congenital systemicto-pulmonary shunts
Box 2 Clinical classification of congenital systemic-topulmonary shunts associated with PAH
1. 1.1. 1.1.1. 1.1.1.1. 1.1.1.2. 1.1.1.3. 1.1.2.
Eisenmenger syndrome
1.2 1.2.1. 1.2.2. 1.3
1.4 1.4.1. 1.4.2. 1.4.3.
1.4.4.
1.4.5. 2. 2.1.
2.1.1. 2.1.2. 2.2. 2.2.1. 2.2.2. 3. 3.1 3.2 3.3 4. 5. 5.1. 5.2. 5.3.
Type Simple pretricuspid shunts Atrial septal defect (ASD) Ostium secundum Sinus venosus Ostium primum Total or partial unobstructed anomalous pulmonary venous return Simple post-tricuspid shunts Ventricular septal defect (VSD) Patent ductus arteriosus (PDA) Combined shunts (describe combination and predominant defect) Complex congenital heart disease Complete atrioventricular septal defect Truncus arteriosus Single-ventricle physiology with unobstructed pulmonary blood flow Transposition of the great arteries with VSD (without pulmonary stenosis) and/or PDA Other Dimension (specify for each defect if more than 1) Hemodynamic (specify ratio of pulmonary-to-systemic blood flow) Restrictive (pressure gradient across the defect) Nonrestrictive Anatomic Small to moderate (ASD 2 cm and VSD 1 cm) Large (ASD >2 cm and VSD >1 cm) Direction of shunt Predominantly systemic-topulmonary Predominantly pulmonary-tosystemic Bidirectional Associated cardiac and extracardiac abnormalities Repair status Unoperated Palliated (specify type of operation(s), age at surgery) Repaired (specify type of operation(s), age at surgery)
From Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54(Suppl 1):S43–54; with permission.
PAH with moderate to large defects
PAH with small defects
PAH following corrective cardiac surgery
Patients with unrepaired systemicto-pulmonary shunts resulting from large, nonrestrictive defects leading to a severe, progressive increase in PVR, bidirectional shunting, and ultimately reversed shunting with central cyanosis PVR is mildly to moderately increased, systemic-topulmonary shunt is still present, and no cyanosis is present at rest Smaller defects generally include VSD 1 cm and ASD 2 cm, and clinical picture is similar to IPAH CHD has been corrected, but PAH is present either immediately after surgery or recurs several months or years after surgery in the absence of significant residual shunts
Abbreviations: ASD, atrial septal defect; CHD, congenital heart disease; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; PVR, pulmonary vascular resistance; VSD, ventricular septal defect. From Simonneau G, Robbins IM, Beghetti M, et al. Updated Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54(Suppl 1):S43–54; with permission.
outcomes than patients with ES, as there is no pop-off mechanism to unload the RV Subgroup 4, postoperative residual or recurrent PAH Some patients develop PAH months or even years following surgery, despite shunt closure being performed at an appropriate age. Although genetic factors may play a role in their predisposition to develop PAH, it is not completely understood why some patients develop PAH even with timely repair of a systemic to pulmonary shunt. Patients with postoperative PAH also act
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Krishnan & Rosenzweig physiologically like IPAH, and need to be treated more aggressively, with strategies similar to those used for IPAH. Manes and colleagues10 analyzed data from 192 patients with APAH-CHD collected over 13 years, and compared the outcomes of different subtypes of APAH-CHD with patients with IPAH. The investigators demonstrated that patients with ES had the highest baseline PVR and lowest exercise capacity. However, they also found a 20-year Kaplan-Meier survival estimate of 87% for ES compared with 36% in postoperative APAH-CHD. Other studies have also shown a favorable prognosis for patients with APAH-CHD as compared with IPAH.9,11,12 However, in 2010, when the long-term outcomes data from the REVEAL study were analyzed, survival in patients with APAH-CHD was not significantly different from that in patients with IPAH.13 This is probably because this study included all 4 subgroups of patients with APAH-CHD and not just the patients with type 1 ES, who appear to have a survival advantage over IPAH and postoperative APAHCHD.10 Management of patients within the first 2 categories, those with Eisenmenger physiology and those with PAH in the setting of unrepaired moderate to large defects, poses added challenges, and is the focus of the remainder of this article. Management of groups 3 and 4 is similar to the management of patients with IPAH.
PAH ASSOCIATED WITH UNRESTRICTIVE SYSTEMIC TO PULMONARY SHUNTS The clinical presentation of APAH-CHD depends on the status of pulmonary vascular disease at the time of evaluation. In patients with large shunts and normal PVR, such as the infant with a large, nonrestrictive VSD, increased PBF, and congestive heart failure, the presentation is usually of failure to thrive, feeding intolerance, resting tachypnea, and recurrent respiratory infections. In these patients, surgical therapy after medical stabilization is the treatment of choice. Even within this group, in about 2% of children with large systemic to pulmonary shunts present, postoperative PAH occurs, with approximately 0.75% suffering PH crises.14 In these patients, mortality remains relatively high at 20% to 30%.14–17 Children at risk for postoperative PAH crises are often those with Down syndrome, complex CHD (atrioventricular canal defects, aortopulmonary window, transposition of great arteries, and truncus arteriosus), and children with very reactive PAH with PH crises in the preoperative period.15 In patients with large systemic to pulmonary shunts presenting at an older age, careful
evaluation to determine operability is critical before repair. Patients with APAH-CHD (see Box 2) with modestly elevated PVR and moderate systemic to pulmonary shunts (type 2) are also quite challenging to manage.18 Determining whether the patient is operable, and if the patient would benefit with pretreatment with targeted therapies is essential, although there are no evidence-based guidelines available. Closing a defect should not be performed just because it can be, but rather only when the PAH is likely to improve after surgical intervention. This is an important point, particularly now that we have data that show that patients with postoperative APAH-CHD fare worse than other forms of APAH-CHD. Cardiac catheterization and acute vasodilator testing remain important tools to help determine safe operability in these patients. Although no validated criteria exist for predicting long-term postsurgical morbidity and mortality, a complete set of hemodynamics should be obtained; vasodilator testing and temporary balloon occlusion of the defect may also be helpful. Obtaining resting room air oxygen saturations and then oxygen saturation following exertion can be helpful in the assessment of operability. For a patient with resting cyanosis or even cyanosis with exertion, closing the defect can lead to worsening right heart failure by removing the pressure/volume “pop-off” that the defect affords the right ventricle. Other important elements of the history include age at diagnosis, current age, and type and size of CHD. The importance of the type of CHD has been previously discussed, and, in general, the earlier a shunt lesion is diagnosed, the more likely the patient is operable. A history suggestive of initial congestive heart failure, including recurrent respiratory infection and effort intolerance, which improves over time to a “honeymoon period” of symptomatic relief, is suspicious of the development of irreversible pulmonary vascular disease with less net left to right shunting. In this situation, exercise testing may reveal latent cyanosis. Elevated hemoglobin in an iron replete patient, suggesting erythrocytosis in response to hypoxia, may also indicate intermittent right to left shunting through the course of the day.
INTERPRETATION OF HEMODYNAMIC DATA Indices of right heart function, including right atrial pressure and cardiac index, are important determinants of prognosis in IPAH.15 In patients with APAH-CHD, PVR also becomes an important tool for the assessment of the patient. It is essential to understand that PAH in patients with large systemic to pulmonary shunts can be due to an
PAH and Congenital Heart Disease increase in PBF or due to an increase in the PVR. In patients with a large unrestrictive VSD or PDA, PAP will be at systemic levels regardless of the PVR because of the increase in PBF (PBF [Qp]:systemic blood flow [Qs]). In contrast, elevation in the PVR is determined by the extent of pulmonary vascular obstructive disease (PVD). Therefore, in patients with APAH-CHD, calculation of the PVR is clinically important as well. In a patient with a large shunt and normal PVR index (PVRi) less than 3 U M2, complete repair of the defect is usually not associated with residual PAH. However, when there is elevation of PVR above 6 U M2, completely repairing the defect can be dangerous and associated with residual PAH and postoperative PH crises and RV strain. During the hemodynamic evaluation of a systemic-to-pulmonary shunt, baseline room air hemodynamics should include 3 complete oxygen saturation runs and pressure measurements in the superior vena cava, right atrium (RA), RV, pulmonary artery (PA), and pulmonary capillary wedge pressures (PCWP). Once baseline data are collected, if there is no elevation of PAWP and PVRi is greater than 3 U M2, acute vasodilator testing should be performed and another full assessment should be performed. Data should be obtained in the absence of respiratory or metabolic acidosis, anemia, or agitation. Nevertheless, the issue of determining operability is not straightforward and has been highlighted in several recent articles.19–21 Lopes and O’Leary21 proposed the following hemodynamic criteria for operability, based on existing literature and surveying centers of excellence with experience in the treatment of pulmonary hypertensive patients: baseline PVRi less than 6 WU M2 and PVR-SVR ratio less than 0.3. Acute vasodilator testing (AVT) was suggested if PVR at baseline was 6 to 9 WU M2 with a PVR-SVR ratio of 0.3 to 0.5. In these patients, a favorable outcome is considered likely if with AVT, the following criteria are met: (1) a decrease of PVRi by greater than 20%, (2) a decrease in PVR-SVR ratio by 20%, (3) a final PVR less than 6 WU M2, and (4) a final PVR-SVR ratio less than 0.3. Other centers have reported higher baseline PVRi values for operability PVRi less than or equal to 7 to 8 WU M2 and PVR-SVR ratios of less than or equal to 0.4.22,23 None of these studies report long-term outcomes following closure of the defects, and the question of the benefits of pretreating with targeted PAH therapies before surgical repair remains unanswered. Cardiac catheterization alone, however, is usually not sufficient to determine operability. The hemodynamic findings must be taken in the context of the medical history, physical examination, and
results of all invasive and noninvasive testing. For example, in a case of borderline PVR at rest in the catheterization laboratory, but with significant exertional cyanosis, shunt repair may be more harmful than beneficial. In patients with “borderline” hemodynamics (eg, PVRi 3 to 6 U M2), there may be an evolving role for a combined medical-surgical approach. Although this has not been proven to provide long-term benefit, there have been anecdotal cases, including at our own institution, of being able to partially repair after using targeted PAH therapy in borderline cases (Fig. 1). It may be reasonable to treat with targeted PAH therapies for a period of months, and serially reevaluate by catheterization to determine operability or partial operability with intentional creation of a small residual defect as a “pop-off.”18–20 In rare borderline patients, medical therapy may drop the PVR enough to increase the left to right shunt to such an extent that there is significantly elevated PBF and the patient develops signs and symptoms of high-output failure.20 As a result, surgical shunt closure should be expeditiously performed to protect the pulmonary vasculature from high flowrelated damage. Surgery on a patient with borderline PAH should be undertaken after careful consideration of all these factors and there should be a multidisciplinary team approach involving the cardiologist, surgeon, intensivists, anesthesiologists, and the postoperative intensive care unit team. Care should be taken to anticipate and avoid PA pressure swings during induction of anesthesia and during recovery. Circulating vasoactive factors from blood products (like platelets) are known to precipitate PAH crises and should be avoided if possible. In the postoperative period, use of pulmonary vasodilators, including inhaled nitric oxide (iNO) and adequate oxygenation, as well as avoidance of respiratory acidosis, is essential. Some patients may require sedation (and/or paralysis) and mechanical ventilation for several days if they have labile PH in the postoperative period. The use of sildenafil while weaning iNO has been found to be effective in preventing rebound PH in some cases.24
EISENMENGER SYNDROME The term “Eisenmenger syndrome” (ES) was coined by Paul Hamilton Wood in 1958 to define the condition of increased PAP and PVR in relation to a VSD with resultant shunt reversal and cyanosis. Currently, the term Eisenmenger physiology has been expanded to include any reversed shunt secondary to elevated PVR, including shunts associated with complex
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Fig. 1. APAH-CHD (ASD) clinical management algorithm: individualized case approach. ASD, atrial septal defect; AVT, acute vasodilator testing; PVR:SVR ratio, ratio of pulmonary vascular resistance to systemic vascular resistance; PVRI, pulmonary vascular resistance indexed to body surface area; TBO, temporary balloon occlusion. (From Rosenzweig EB, Barst RJ. Congenital heart disease and pulmonary hypertension: pharmacology and feasibility of late surgery. Prog Cardiovasc Dis 2012;55(2):128–33; with permission.)
CHD.25 With timely CHD diagnosis and cardiac surgery, especially during infancy, survival of patients into adulthood is commonplace, and the worldwide incidence of ES has declined by 50%.26,27 However, ES still remains a significant problem in the developing world, where patients with large shunts are unable to undergo repair before the development of PVD. The worldwide prevalence of PAH in adults with CHD has recently been estimated at between 1.6 and 12.5 million, with 25% to 50% presenting with ES.28 Although life expectancy is reduced in ES, it is significantly better than IPAH, with many patients with ES surviving into their third and fourth decades, and even some into their seventh decade.26,27 More than 40% of subjects are expected to be alive 25 years after diagnosis. Fig. 2 shows the Kaplan-Meier curves of life expectancy in simple versus complex lesions leading to ES.29 Patients with complex lesions have a much worse prognosis than those with simple shunts. However, with advances in targeted therapies, the outlook for patients with ES may improve, as a recent study predicted Kaplan-Meier survival estimate at 20 years of 87% in patients with ES.10 The presentation and clinical course of ES are a result of chronic hypoxia and are different from those of IPAH. Patients with ES often have
objective evidence of significant effort intolerance, but may not perceive their limitation because of the chronicity of their disease. Their symptoms and complications are secondary to the cyanosis, erythrocytosis, and end-organ damage. On physical examination, central cyanosis with clubbing
Fig. 2. Survival prospects of patients with Eisenmenger physiology when compared with an ageand gender-matched healthy population showing reduced life expectancy in patients with ES. y, Predicted survival is based on the life tables for UK and Wales (2001–2003 interim life tables) published by the Government Actuary’s Department. *, Comparison between Eisenmenger patients with simple and complex lesions. Patients with complex lesions had a significantly worse outcome compared with those with simple lesions.
PAH and Congenital Heart Disease may be present, RV heave and a prominent second heart sound are often present, and hepatomegaly and peripheral edema may be appreciated in more advanced cases. Patients may also present with serious complications, such as cerebral abscess or stroke, pulmonary arterial thrombosis, massive hemoptysis due to rupture of thin-walled pulmonary vessels, bacterial endocarditis, or severe myocardial dysfunction with low cardiac output.
MANAGEMENT STRATEGIES FOR ES In the past, treatment options for patients with ES had been limited to palliative therapies and heartlung transplantation or lung transplantation with repair of the CHD. However, over the past decade, there has been growing experience using both conventional and targeted PAH therapies in patients with ES. Commonly used conventional therapies include digoxin, diuretics, anticoagulation, and antiarrhythmics, although none of these have been shown to improve survival in ES. Anticoagulation in patients with ES remains controversial because of increased risks of pulmonary artery thrombosis, as well as hemoptysis, stroke, and hemorrhage. Although the benefit of anticoagulation in patients with IPAH has been demonstrated, no such data exist for patients with ES, and, given the potential complications, the decision to anticoagulate should be made carefully on an individual case basis. Oxygen is often used long term in patients with ES, and although it may be associated with improvement in subjective status, no survival benefit has been seen. Maternal mortality in patients with ES is reported at approximately 50%, with death usually occurring during delivery or the first postpartum week due to hypervolemia, thromboembolism, or preeclampsia. In addition, spontaneous abortion rates are quite high, and for infants carried to term, there are high rates of intrauterine growth retardation and perinatal mortality.29–31 As a result, pregnancy is contraindicated in ES.
TARGETED THERAPIES FOR ES There are 3 main classes of targeted PAH therapies initially used in patients with group 1 PAH, and currently, all have been used in the treatment of patients with ES. These include prostanoids, endothelin receptor antagonists (ERAs), and phosphodiesterase-5 (PDE5) inhibitors. The aim of targeted therapies in patients with ES is to improve exercise tolerance by improving PBF, hypoxemia, physical capacity, and, ultimately, survival.
Prostanoids The use of intravenous epoprostenol in ES was first described by Rosenzweig and colleagues32 in 1999, with subjects showing improvements in functional capacity, hemodynamics, and survival. Because epoprostenol is chemically unstable at neutral pH/room temperature, and has a short half-life (1–2 minutes), a continuous intravenous delivery system with cold packs is needed to maintain stability. An indwelling central venous line is necessary, with associated complications, including thrombosis and line occlusion, local and systemic infection, and catheter breakage. The risk of thromboembolism is of particular concern in patients with ES with right to left shunts. In addition, pump malfunction may rarely lead to administration of a sudden bolus of epoprostenol (leading to systemic hypotension) or interruption of the medication, which can cause severe rebound PAH. Therefore, a search for alternate routes of drug delivery has led to the approval of inhaled (iloprost, treprostinil), subcutaneous (treprostinil), and more stable and longer-acting intravenous prostacyclin analogues (treprostinil, veletri). Treprostinil sodium is a prostacyclin analogue with a neutral pH, longer half-life, which is stable at room temperature, and shares the same pharmacologic actions as epoprostenol with potential advantages by being able to deliver the agent via inhalation or subcutaneous infusion, thus eliminating the risk of thromboembolic events in patients with ES.33
ERAs Endothelin (ET)-1 is one of the most potent vasoconstrictors implicated in the pathobiology of PAH and plasma ET-1 levels are increased in patients with IPAH (and other forms of PAH) and correlate inversely with prognosis. The first randomized, double-blinded, placebo-controlled study in patients with ES was the Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) trial investigating the efficacy and safety of the dual ERA bosentan in patients with ES.34,35 During the 16-week study, bosentan significantly reduced PVR, and improved PAP and exercise capacity compared with placebo without worsening oxygenation, and longer-term data from the follow-up portion of the study demonstrated continued improvements in exercise capacity over an additional 24 weeks.35 The study also demonstrated a worsening of PVR in the placebo group, which underscores the progressive nature of untreated ES. Risks associated with ERAs include acute hepatotoxicity (bosentan), teratogenicity, and possibly male
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Krishnan & Rosenzweig infertility. The selective ERA ambrisentan may offer potential advantages over bosentan, given its selectivity for the ET-A receptor, which demonstrates vasoconstrictor effects, although this remains controversial. Ambrisentan, which can be administered once a day, was also found to be efficacious in a series of patients with ES with an acceptable safety profile.36
PDE5 Inhibitors PDE5 inhibitors prevent the inactivation of cyclic guanosine monophosphate (GMP), thereby raising cyclic GMP levels. Oral sildenafil is the most widely used of the PDE5 inhibitors in the treatment of PAH, and has been used in children with APAH-CHD, with benefits on exercise capacity and hemodynamics.37 In a recent prospective, open-label, multicenter study, using sildenafil, patients with ES demonstrated an acceptable safety profile and improved exercise capacity, oxygen saturation, and hemodynamics after 12 months of therapy.38 A recent randomized, placebo-controlled, double-blinded crossover study using tadalafil in patients with ES also demonstrated safety and short-term improvements in exercise capacity, functional class, oxygen saturation, and hemodynamics after 6 weeks of therapy.39
Lung and Heart Lung Transplantation Currently, the overall 1-year, 5-year, and 10-year survival for lung transplantation for patients with PAH is 64%, 44%, and 20%, respectively.40–42 For patients with untreated ES, the 5-year and 25-year survival is greater than 80% and 40%, respectively as opposed to following lung transplantation (52% and 39%).40–42 Thus, lung transplantation should be reserved for patients with WHO functional class IV symptoms with an estimated likelihood of survival of less than 50% at 5 years. Although lung and heart/lung transplantation are imperfect therapies for pulmonary arterial hypertension, when offered to an appropriately selected population, transplantation may improve survival with an improved quality of life. The use of extracorporeal membrane oxygenation as a bridge to recovery (in acutely decompensated patients), as well as a bridge to transplantation, may also be a viable option in selected patients.42
PULMONARY HYPERTENSION IN THE UNIVENTRICULAR HEART: THE FAILING FONTAN The Fontan (total cavopulmonary connection) circulation, which is surgically created for
hypoplastic left heart syndrome, lacks a pumping subpulmonary ventricle, and is dependent on the central venous pressure to perfuse the pulmonary circulation. Thus, changes in the PVR can have a tremendous impact on forward flow in this circulation. For patients with a single ventricle, the hemodynamic criteria used for shunt closure do not apply for predicting operability. Pre-Fontan PVRi should be normal in these patients, to sustain the cavopulmonary circulation (ie,
