Curr Treat Options Cardio Med (2014) 16:328 DOI 10.1007/s11936-014-0328-z

Adult Congenital Heart Disease (A Bhatt and K Niwa, Section Editors)

Pulmonary Hypertension in Adult Congenital Heart Disease Josanna Rodriguez-Lopez, MD Address Division of Pulmonary and Critical Care, Mass General Hospital, 55 Fruit Street, BUL 148, Boston, MA 02114, USA Email: [email protected]

* Springer Science+Business Media New York 2014

This article is part of the Topical Collection on Adult Congenital Heart Disease Keywords Adult congenital heart disease I Pulmonary hypertension I Atrial septal defect I Ventricular septal defect I Eisenmenger syndrome I Congenital heart disease surgical repair I Right ventricular catheterization I Endothelin receptor antagonist I Phosphodiesterase-5 inhibitors I Prostacyclins

Opinion statement There is a growing patient population with adult congenital heart disease that needs specialized medical attention and careful long-term evaluation. Pulmonary arterial hypertension (PAH) associated with congenital heart disease (PAH-CHD) is a common late complication, and is associated with increased morbidity and mortality. There are no clear current guidelines for the treatment of PAH-CHD. There are few trials to date investigating PAH treatment specifically in this group of patients. However, the available data seems to demonstrate that with the advent of PAH-targeted therapies, the quality of life, exercise capacity, and outcomes in these patients is improving. In addition, PAH-targeted therapies may be useful in select patients for a combined medical-surgical approach to treatment. Here we discuss the epidemiology and pathophysiology of PAH-CHD, current therapies, and the data supporting their use, and how to evaluate feasibility of late surgical repair.

Introduction Pulmonary arterial hypertension (PAH) is a serious complication of adult congenital heart disease (CHD). It develops as a result of vascular remodeling secondary to increased pulmonary blood flow, increased pressures in the pulmonary vasculature from left to right shunting, and sheer stress. Improvements

in the management of pediatric congenital heart disease have led to an expanding patient population that survives to adulthood and requires life-long medical care. Without surgical repair of CHD, it is estimated that about one-third of patients would develop significant PAH [1]. Despite great advances in pediatric car-

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diology and surgery, about 5 – 10 % of these patients still develop pulmonary arterial hypertension, which leads to increased morbidity and mortality [2, 3, 4•]. With the introduction of new pulmonary hyperten-

sion-specific therapies and better pathophysiologic understanding of the disease, adult patients with congenital heart disease and associated PAH can benefit from improved quality of life and survival.

Definition Pulmonary arterial hypertension (PAH) is defined as an elevated mean pulmonary arterial pressure greater than 25 mmHg, with normal left sided filling pressures, (i.e. left ventricular end diastolic pressure, left atrial pressure, or pulmonary capillary wedge pressure of less than 15 mmHg) [5]. PAH may be idiopathic, familial, or associated with other conditions such as congenital heart disease, portal hypertension, HIV, connective tissue disease, and drugs or toxins [5, 6]. Therefore, pulmonary hypertension secondary to congenital heart disease is considered an associated condition. While the most recent expert consensus excluded pulmonary vascular resistance (PVR) in the definition of PAH [5], it is important to determine pulmonary vascular resistance when evaluating a patient with congenital heart disease-associated PAH (PAH-CHD). Increased pulmonary blood flow in CHD may result in elevated pulmonary pressures. However, in the absence of an elevated PVR 9 3 Woods Units, elevated pulmonary pressures may be reversible, secondary to increased flow, and may not represent a true pulmonary vasculopathy. When diagnosing patients with PAH-CHD, it is also important to rule out pulmonary venous (or post-capillary) hypertension.

Epidemiology A number of different cardiac defects can lead to the development of PAH, and most cases develop as a consequence of large systemic-to-pulmonary shunts. The Dutch CONCOR registry found a prevalence of 4.2 % PAH-CHD among 5,970 patients with CHD. The prevalence of PAH-CHD was higher (6.1 %) among patients with septal defects, of which 58 % had Eisenmenger syndrome. The prevalence is lower (3 %) in those who had a previously closed septal defect. The prevalence of PAH-CHD also depends on the type of septal defect: of the 41 % atrioventricular septal defects, 11 % were VSDS, 8 % were secumdum ASDs, and 7 % were primum ASDs [7]. Ventricular septal defects (VSD) are the most common form of CHD, with an estimated prevalence of three per 1,000 children [8]. It is the most common lesion of CHD with associated PAH. In the CONCOR registry, 42 % of patients with PAH-CHD had a VSD, and 79 % of VSD patients with PAH had Eisenmenger sydnrome [7]. A larger retrospective Canadian study from 1983 – 2005 found that out of 38,430 adults with CHD, 5.8 % developed PAH-CHD. Of the patients who developed PAH-CHD, 38 % had septal defects. The likelihood of developing PAH-CHD also depends on whether or not a defect is repaired [9]. There are certain lesions such as truncus arteriosus, atrioventricular canal defect, and transposition of the great arteries with VSD, which undoubtedly develop PAH if not repaired during infancy. Large

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ventricular septal defects and patent ductus arteriosus will develop PAH 50 % of the time if not repaired by 2 years of age. On the other hand, pretricuspid lesions can be repaired later on in life or early adulthood. Large ASDs are variable, with about 10 % developing PAH-CHD if not repaired by adulthood [9]. Lesions that are repaired late have a higher likelihood of developing PAH-CHD in adulthood. The most extreme form of PAH-CHD is Eisenmenger syndrome. It is characterized by severe PAH leading to systemic pulmonary pressures and reversal of shunt. With better surgical therapies and earlier recognition of CHD, Eisenmenger syndrome has decreased in frequency from about 8 % of all CHD [10] to about 4 % [7, 11].

Pathophysiology PAH-CHD is caused by increased pressure and blood flow through the pulmonary circulation due to shunting via an abnormal connection or defect. In post-tricuspid valve lesions such as VSDs and PDAs, the pulmonary vasculature is constantly exposed to systemic pressures. In pre-tricuspid valve lesions, those at the atrial or venous level, it is not high pressure, but high volume and flow, which circulates through the RV and pulmonary vasculature. In time, both the increased pressure and or volume, results in endothelial damage, vascular remodeling, smooth muscle cell hypertrophy, and activation of inflammatory and prothrombotic pathways [2] [12]. Endothelial dysfunction will in turn lead to increased production of vasoconstrictors (such as endothelin-1 and thromboxane) and decreased production of vasodilators (such as nitric oxide and prostaglandins) [2]. This creates an imbalance in vasoactive mediators which promotes vasoconstriction and increased pulmonary vascular resistance.

Eisenmenger syndrome In severe cases, as pulmonary vascular resistance increases, there is reversal of flow with shunting from right to left and notable cyanosis. This is called Eisenmenger syndrome (ES). It is the most severe type of PAH-CHD and is an end-stage complication. Once a patient develops ES, surgical repair of CHD is contraindicated and could be fatal. ES differs from other types of PAHCHD in physiology and prognosis. In large unrestricted shunts, the direction and volume of shunt is determined by pressure differences between systemic and pulmonary circulations. In pre-tricuspid lesions, the pathophysiology of ES can be different. Reversal of flow from right to left in an ASD is not always secondary to suprasystemic pulmonary pressures. It can develop as a result of decreased right ventricular compliance secondary to right ventricular hypertrophy and RV diastolic dysfunction. Therefore, ES is rarely seen in pre-tricuspid valve lesions. If it does occur, it happens much later in life, once the RV has had time to remodel and hypertrophy [2, 9, 13]. Conventional therapies such as anticoagulation and long-term oxygen use have not been found to improve outcomes. There are no data on safety, benefit, or risk of anticoagulation in ES, and anticoagulation remains controversial. ES is associated with 20 % risk of intrapulmonary thrombosis [14], but there is also a significant risk for hemoptysis, pulmonary infarct, and

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Curr Treat Options Cardio Med (2014) 16:328 stroke [3]. The risk and benefit of anticoagulation should be decided on a case by case basis. In addition, long-term oxygen has not been extensively studied in this population. One study using nocturnal oxygen did not show improvement in exercise, quality of life, or survival [2, 15]. In some patients, oxygen supplementation may improve symptoms and should be considered.

Anatomy The risk of developing PAH-CHD is dependent on different anatomic variables which need to be characterized when evaluating a CHD adult patient (Table 1). These variables include defect type, defect size, net directionality of shunt, and repair status and timing [9]. Pre-tricuspid lesions have a lower risk of developing PAH-CHD than post-tricuspid valve lesions. These include ASD (primum, secundum, or sinus venosus) and anomalous pulmonary venous return [16, 17]. Secundum ASD is the most common type of pre-tricuspid defect, accounting for about 75 % of all ASDs. It involves the region of the fossa ovalis and is a true defect of the atrial septum. It has the lowest risk of PAH-CHD [18]. ASD primum is within the spectrum of AV septal defects, as it involves the inferior aspect of the atrial septum, near the atrioventricular valve. It is the second most common type of ASD and has the highest risk of developing PAH-CHD. Sinus venosus ASD is the least common type of ASD and has intermediate risk of PAH-CHD. The defect is located at the junction of the SVC and the right atrium, and is usually associated with partial anomalous pulmonary venous return. In general, larger ASDs, those greater than 2 cm, have a higher risk of PAH-CHD than smaller ones. Partial anomalous pulmonary venous return is similar to an ASD in that it is a low pressure pre-tricuspid valve lesion which increases flow and volume to the RV and pulmonary circulation, without exposing them to increased pressure. Independently, it is a rare lesion, found in about 0.6 – 0.7 % of routine autopsies [17]. Post-tricuspid defects can be simple defects, such as VSDs and patent ductus arteriosis (PDA), or complex defects. VSDs can be classified as membranous, muscular, inlet, or outlet. Inlet VSDs are surrounded by the mitral valve, tricuspid valve, and muscular septum, and are, therefore, part of the spectrum of AV canal/septal defects. They are often associated with trisomy 21 and are the most common type of VSD associated with PAH-CHD [8]. The size of the VSD also affects the risk of developing PAH-CHD. Defects of less than 1 cm or 25 % of the diameter of the aortic annulus are considered small, restrictive defects. Large,

Table 1. CHD and Risk of PAH-CHD Pre-Tricuspid Lesions Post-Tricuspid Lesions

Low Risk

Intermediate Risk

High Risk

• Secundum ASD • Partial Anomalous Venous Return • Small Restrictive VSD

• Sinus Venosus ASD

• Primum ASD • Large Unrestricted VSD • PDA • AV Septal Defect

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unrestricted defects, measuring more than 1 cm, have a greater degree of systemic to pulmonary shunting, exposing the pulmonary vasculature to systemic pressures and more likely leading to PAH-CHD [9]. Patent ductus arteriosis (PDA) are less common than septal defects, and represent about 5 – 10 % of congenital heart defects [17]. A PDA is a physiologic abnormality, rather than a structural abnormality, that is needed for fetal circulation. It usually closes a few days after birth, with 75 % of PDAs closing by 3 months of age [17]. In rare cases, it can stay patent and lead to systemic to pulmonary shunting. Those that fail to close should be repaired before 1 – 2 years of age to prevent development of PAH-CHD. Similar to a VSD, PDA creates a high-pressure to low-pressure shunt which can lead to pulmonary vascular disease. Development of PAH-CHD depends on the size of the PDA and the degree of shunting. About 3 – 20 % of PAH-CHD patients are secondary to a PDA, making it the third most common defect associated with PAH-CHD [7]. Complex CHD defects include atrioventricular septal defects, truncus arteriosis, single-ventricle physiology, and transposition of the great arteries with VSD [6]. If not repaired, complex congenital heart defects have the highest risk of developing PAH-CHD early in childhood. Aortopulmonary window, similar to a PDA, is an abnormal connection between the ascending aorta and the main PA. It is usually a large and unrestricted shunt that if not corrected will progress to ES. Truncus arteriosus, transposition of the great arteries and double outlet RV will also result in ES if not corrected early. The subaortic subtype of double outlet RV is the most common type (about 50 % of cases) associated with PAH-CHD as its pathophysiology is similar to a large VSD. Previously used palliative systemic to pulmonary artery shunts such as Waterston or Potts shunts, can also result in PAH-CHD [19]. Repair status is crucial in understanding the pathophysiology and risk of developing PAH-CHD. Defects that have been repaired at an early age can still develop PAH-CHD, although the risk is lower. An adult with an unrepaired defect will have a greater likelihood of progressing to PAH-CHD and to Eisenmenger syndrome given persistent elevated pressure and flow through the pulmonary circulation over time. However, a “late” repair in the setting of an elevated PVR can also progress to PAH with a clinical picture more consistent with IPAH than PAH-CHD [9]. PAH-CHD can develop months to years after the surgical repair, even in the absence of residual shunt. Post-repair PAH-CHD with no residual defect will have an identical picture to IPAH and should be treated the same way.

Surgical repair A CHD defect discovered in adulthood should not be automatically corrected. A thorough evaluation by a pulmonary hypertension specialist in conjunction with an adult congenital heart specialist should be done prior to any surgical intervention. Correcting a defect on the wrong patient could lead to progression of pulmonary hypertension, right ventricular failure, and worse prognosis than prior to repair. Since there are now effective medical treatments for PAH, a combined medical and surgical approach can be considered in some adult patients with uncorrected CHD (Table 2).

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Table 2. Defect Type and Treatment Options [9, 26] Type of Defect Small Restrictive Defects (ASDG2 cm, VSDG1 cm) with normal PVR (G3 WU) and net left-to-right shunting

• No contraindication for closure

Moderately restrictive defect in patients who have not undergone • Treat with advanced therapies closure and have mild to moderately elevated PVR (3 – 6 WU), • Rule out desaturation with exercise • Serial right heart catheterizations with vasodilator but no cyanosis and exercise testing • Consider closure or partial closure (with fenestration) if on treatment: • PVR G3 WU • No desaturation with exercise • Qp:Qs between 1.6:1 and 2:1 • PAH reversible with vasodilator therapy • PAPG2/3 Systemic BP, PVRG2/3 SVR • Tolerates temporary occlusion in catheterization lab Large nonrestrictive defects (ASD92 cm, VSD91 cm) in cyanotic • Closure contraindicated patients with elevated PVR and shunt reversal (right to left) • Treat with advanced therapies for PAH Defects previously closed in childhood, now with elevated PVR and evidence of irreversible PAH

• Treat with advanced therapies for PAH

Patients being considered for surgery should get a right heart catheterization to measure hemodynamics at rest and with exertion [9, 20]. Hemodynamic measurements should be repeated after vasodilator testing. A shunt study should be performed to evaluate degree of shunting and blood flow through the pulmonary circulation, Qp/Qs. In IPAH, right atrial pressure and cardiac index are the most important indices of pulmonary hypertension severity. In adult CHD, pulmonary vascular resistance (PVR) and Qp/Qs are more important indicators of severity of disease and reversibility with surgery. The mean pulmonary artery pressure is not important, since most of these patients have very high or systemic pulmonary pressures. This can be secondary to large systemic-to-pulmonary shunting vs. a true vasculopathy, which would be indicated by an elevated PVR. Making this distinction is crucial when evaluating for surgery. High pulmonary pressures due solely to high Qp/Qs, with a normal or low PVR, are potentially reversible when a defect is corrected. On the other hand, high pulmonary pressures secondary to a high PVR would be a contraindication for surgery. This distinction may be difficult to make since many of these patients can have a mixed picture, making the decision on whether or not to operate more complicated. When evaluating for closure of a defect, the age of the patient and the size of the defect need to be considered. A small child with a large defect, who has normal PVR and mPAP, should undergo closure. On the other hand, an adult with cyanosis at rest or with exertion should probably not undergo closure, as this is a sign of advanced PAH-CHD and reversal of shunting. It is the more complicated cases that require careful evaluation, for example, an adult

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with a moderate to large uncorrected defect with elevated mPAP, but normal to slightly elevated PVR, and mostly systemic-to-pulmonary shunting (Qp/ Qs 1.5:1-2;1) (Table 2). In such cases, medical treatment with PAH therapy, serial catheterizations, and temporary balloon occlusion of the defect should be considered prior to committing to closure. If a defect is deemed operable, a patch with a small fenestration can be considered. This could act as a “popoff” valve if the patient has worsening pulmonary hypertension after surgery [9]. Closure of the residual defect can then be considered after the post-operative period. If treatment with PAH therapy is needed to have acceptable hemodynamics pre-operatively, it should be continued and may need to be up-titrated during the post-operative period. There are little data regarding specific hemodynamic parameters used in determining operability in PAH-CHD. A recent extensive review suggested that that PVR valuesG6 WU can be considered operable, although these numbers should be used as a guide and not an absolute [21]. A more conservative approach would be to accept only a normal PVR G3 WU, prior to surgical correction. This could be achieved either with PAH therapy or vasodilator therapy in the catheterization lab. The ability to reduce the PVR to G6 WU or lower with vasodilator testing, and having a PVR/SVR ratio ofG0.3, have also been associated with improved outcomes [21, 22]. In patients that are borderline operable, the best strategy is to treat with targeted therapy and re-evaluate. Patients with severe pulmonary vascular disease, cyanosis at rest or with exertion, and/or overt ES should not be considered for closure. These patients should be treated with targeted PAH therapy alone. Operating on the wrong patient could lead to postoperative complications including PH crisis, RV failure, and death. In addition, development of worsening PAH after surgical closure can have a worse prognosis (similar to IPAH) than PAH-CHD before correction [5]. Residual defects can be present years after an initial operation and can be the cause of PAH-CHD decades later. Sometimes these defects are amenable to reoperations, although with greater risks than the primary surgery given adhesions and longer cardiopulmonary bypass time [23, 24]. A less invasive option for primary or secondary repair in adult CHD is percutaneous transcatheter interventions. Surgical intervention, once the mainstay of corrective therapy, has recently been replaced by less invasive transcatheter techniques, specifically in secundum ASDs, PDAs, and VSD closures [25]. However, a sinus venosus, coronary sinus, or primum ASD should be repaired surgically rather than by percutaneous closure [26]. The same careful evaluation needs to be completed, regardless of whether a patient undergoes surgical repair or transcatheter repair. Patients with severe PAH, elevated PVR, significant right-to-left shunting, or those who don’t improve with transient balloon occlusions, are generally not considered candidates for transcatheter closures [25, 26]. In carefully selected patients, transcatheter interventions have excellent outcomes and can be used as a primary closure or repeat closure of a persistent defect after surgery [27–30].

Targeted medical therapy The treatment of pulmonary arterial hypertension has greatly advanced in the last decade. There are currently nine drugs approved in the

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Curr Treat Options Cardio Med (2014) 16:328 United States for the treatment of PAH, with a few more being currently evaluated by the FDA. They belong to three drug classes: phosphodiesterase-5 inhibitors, endothelin receptor antagonists, and prostacyclins [5]. Unfortunately, most of the landmark trials for PAH therapy only included a small number of PAH-CHD patients. However, due to the similarities in pathophysiology between IPAH and PAHCHD, all of the targeted therapies are used and approved for the treatment of PAH-CHD. The first prospective observational cohort in PAH-CHD included 21 patients on IV epoprostenol. Treatment with IV epoprostenol resulted in improvement in hemodyamics, functional class, and exercise capacity after 1 year [20]. A large double–blind, placebo-controlled, randomized trial of 470 PAH patients treated with subcutaneous treprostinil vs. placebo also showed improvement in exercise capacity. In this study, 25 % of the patients had PAH-CHD. Randomized trials with sildenafil (SUPER-1) and tadalafil (PHIRST) included 7 % and 12 % PAH-CHD patients, respectively [31, 32]. They both found improvements in exercise capacity in the treatment arms. The initial trials for endothelin receptor antagonists did not include PAHCHD patients. Advanced therapies targeting PAH have been shown to improve hemodynamics, quality of life, and survival in patients with ES [33, 34•]. The BREATHE-5 study was the first and only large randomized, double-blind, placebo-controlled trial in ES patients [35•]. Fifty-four patients with ES, functional class III, were randomized to bosentan vs. placebo for 16 weeks. Treatment with bosentan did not worsen oxygenation and improved functional status and exercise capacity. These findings persisted during a 24-week open-label extension [36]. The placebo group had worsening PVR, indicating that if left untreated, the disease progressed. There was no significant difference between ASD and VSD patients in a subgroup analysis [37]. Ambrisentan, another endothelin receptor antagonist, was also found to be safe and effective in a small observational retrospective study of ES followed for 2.5 years [38]. Other small studies have also looked at the efficacy of additional PAH drugs for ES patients. A retrospective trial of eight ES patients on IV epoprostenol found improvements in oxygenation, 6-min walk distance, and hemodynamics after 3 months of treatment [39]. A randomized, placebocontrolled, double-blind crossover study of 10 IPAH and 10 ES patients found improvement in exercise capacity when treated for 6 weeks with sildenafil, with no significant side effects [40]. A larger open-label study of 84 functional class III-IV ES patients found improvement in 6-min walk distance and oxygenation when treated with sildenafil for 12 months [41]. Tadalafil is less well-studied in this population. One small randomized trial of 28 ES patients followed for 6 weeks showed some improvement in exercise capacity and functional class [42]. In PAH there has been recent interest in the efficacy of combination therapy, and there are multiple ongoing trials exploring this. The only randomized crossover study in ES patients included 21 patients on open-label bosentan. After 3 months of therapy, the addition of sildenafil did not add significant improvement in 6-min walk distance, but did show some improvement in oxygenation by 5 % [43]. Another study looked at 32 PAH-

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CHD patients who were clinically deteriorating on bosentan. Twenty-eight of the 32 had ES, and all received additional therapy with sildenafil. All patients tolerated the combination therapy and had improvements in exercise capacity, hemodynamics, and functional class after 6 months of combination therapy [44].

Prognosis PAH-CHD is a well-recognized complication of adult CHD, and it is an important cause of morbidity and mortality in this patient population. Development of PAH-CHD is associated with at least a twofold increase in morbidity and mortality [4•]. In 2007, there were 84,308 adult CHD hospital admissions in the U.S., of which 54 % had septal defects [45]. On multivariate analysis, independent risk factors for increased mortality were the presence of a VSD and the presence of pulmonary hypertension. A retrospective longitudinal cohort of 38,430 adults with CHD compared mortality and morbidity outcomes between CHD patients with and without PAH-CHD4. The presence of PAH-CHD increased the all-cause mortality rate by more than twofold compared to those without PAH-CHD (HR 2.69). The rate of comorbid complications and utilization of inpatient and outpatient services was threefold higher in PAH-CHD patients. Historically, when compared to other patients with PAH, PAH-CHD patients have a better prognosis [5]. The difference in prognosis is thought to be due to better long-term adaptation of the right ventricle to systemic pulmonary artery pressures. Contrary to prior data, recent outcome data from the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) did not find any significant improved 4- and 7-year survival rates in patients with PAH-CHD versus IPAH [46]. The prognosis of ES is worse than for PAH-CHD without ES. Mortality increases with age and has been found to be as high as 6 %, 26 %, and 48 % at 40, 50, and 60 years of age respectively [13]. When compared with healthy people, the median survival is reduced by 20 years. Predictors of mortality in this group include complex lesions, low functional class, and signs of heart failure, presence of arrhythmias, and low albumin and potassium [13]. Echocardiographic parameters of RV function and RA size also predict mortality in ES patients [47]. A longitudinal study of 181 ES patients found tricuspid annular plane systolic excursion, myocardial performance, elevated right atrial pressure, and ratio of right-to-left atrial area to be the strongest predictors of mortality, even after accounting for advanced therapy use. Other smaller studies have shown that certain biomarkers, including vWF and BNP, may also help predict mortality in ES patients [48, 49], although it is unclear how useful these markers are in clinical practice. Nevertheless, during the last decade exercise capacity, quality of life, and survival in ES has greatly improved with the addition of targeted advanced PAH therapies [33, 34•]. A single-center retrospective cohort of ES patients found 29 % received targeted PAH therapy [34•] (74 % bosentan, 25 % sildenafil, 1 % epoprostenol, and 6 % combination

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Curr Treat Options Cardio Med (2014) 16:328 therapy). Patients on PAH therapy had significantly lower risk of death (HR 0.16) than those not on therapy, even after adjusting for baseline clinical characteristics.

Conclusion Advances in the care of children with CHD have resulted in a large population of adults with CHD. PAH-CHD is a common complication in these patients, and is associated with increased morbidity and mortality. PAH-CHD patients are a very heterogeneous group with respect to anatomic, physiologic, and clinical features. PAH-CHD needs to be screened for and recognized early on. Although further investigation is needed, improvements in advanced therapies for PAH seem to be improving outcomes in patients with PAH-CHD. The use of advanced therapies has also made it possible for a select group of PAH-CHD patients to undergo surgical repair later on in life. These patients should undergo careful screening by a PAH specialist prior to any intervention.

Compliance with Ethics Guidelines Conflict of Interest Dr. Josanna Rodriguez-Lopez declares no potential conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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Pulmonary hypertension in adult congenital heart disease.

There is a growing patient population with adult congenital heart disease that needs specialized medical attention and careful long-term evaluation. P...
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