Introduction
The prevalence of congenital heart disease (CHD) is about 9 per 1,000 newborns.^1,2 Medical, surgical, and technological advances over the past several decades have allowed the majority of patients with CHD to survive into adulthood.³ As a result, the number of adults with CHD exceeds the number of children with CHD.³ Pulmonary hypertension (PH) is an important prognostic indicator in patients with CHD.⁴ Generally, outcomes of PH due to CHD have improved given advances in pulmonary arterial hypertension (PAH) therapy.⁵

Classification
PH is currently defined as an invasive measurement of mean pulmonary artery pressure (PAP) greater than 20 mmHg.⁶ PH is further subdivided into five subtypes based on the World Health Organization (WHO) classification system. PH due to CHD can be classified as WHO Group 1 or PAH (e.g., Eisenmenger syndrome), WHO Group 2 (e.g., congenital mitral stenosis or Shone complex with multiple left-sided obstructive lesions with elevated left atrial pressure), WHO Group 4 (e.g., pulmonary artery stenosis in Alagille Syndrome), or WHO Group 5 (e.g., complex CHD-like segmental PH, single ventricle).

Upon hemodynamic assessment, PAH will have an elevated mean PAP greater than 20 mmHg as well as a pulmonary vascular resistance (PVR) of 3 Wood units or greater. This elevated PVR is due to obstructive pulmonary vasculopathy, which is mainly driven by the patient's genetic background, modifier genes, vascular shear stress, and environmental triggers.⁵ It is vital to distinguish PAH in CHD from WHO Group 2 PH in which left-sided filling pressures are greater than 15 mmHg because this group does not respond to PAH therapies. The approach to CHD in other WHO subgroups is more specific and is based on underlying disease process.

Diagnostic Workup
Every adult patient with CHD with a diagnosis of PH should be seen at an expert center and undergo a medical history and physical examination. Diagnostic workup is suggested in Table 1.

Table 1: Diagnostic Workup

Test	Indication	Role of Testing
Pulmonary function testing	All patients should receive pulmonary function testing.	Evaluate for lung disease.
Laboratory testing	All patients should undergo laboratory workup.	Evaluate for anemia, iron deficiency, HIV infection, and rheumatoid abnormalities.
Transthoracic echocardiography (TTE)	All patients should undergo TTE.	Evaluate for right ventricular and left ventricular systolic function, left ventricular diastolic function, right ventricular outflow tract obstruction, and pulmonic stenosis.
Cardiac magnetic resonance imaging or cardiac computed tomography	This can be used in conjunction with TTE or in cases of non-diagnostic TTE images.	Quantify ventricular systolic function, evaluate for pulmonic or branch pulmonary artery stenosis, visualize collaterals, and obtain flow-based shunt fraction or Qp:Qs.
Right heart catheterization with compartmental oximetry	All patients should undergo right heart catheterization when making major decisions such as initiation of therapy, change in therapy, in pregnancy, or prior to surgery.	Accurately determine pulmonary artery, right heart and left heart pressures, calculate PVR, and perform vasoreactivity testing.

Therapeutic Management

1. It is recommended that patients with PAH in CHD be cared for by a multidisciplinary team consisting of experts in cardiology, imaging, pulmonology, obstetrics, anesthesiology, neonatology, PH, cardiothoracic and thoracic surgery, nursing, and medical genetics. All patients with PAH in CHD should be given social and psychological support, be kept up to date on their vaccinations, and be advised to avoid excessive physical stress.
2. All female patients with pre-capillary PH should be counseled against pregnancy (Class Ic recommendation).
3. Oxygen supplementation is generally recommended only when arterial blood oxygen pressure is consistently less than 60 mmHg.⁵
4. In patients with Eisenmenger syndrome, specifically, oxygen supplementation should be used only in cases in which there is a documented, consistent, and significant increase in oxygen saturation and improvement in symptoms. Routine phlebotomy should be avoided in these patients because secondary erythrocytosis is expected and, in fact, beneficial because this aides in oxygen transport and delivery.
5. Anticoagulation with vitamin K antagonists should be considered only in patients with concomitant atrial arrhythmias, mechanical heart valves, or vascular prostheses. There are no data on the use of non-vitamin K antagonist oral anticoagulant therapy in this patient population. The risk of bleeding does increase in cyanotic patients, so the use of oral anticoagulation and antiplatelet agents should be made on a case-by-case basis and with great consideration.
6. Advanced therapies for PAH have been shown to benefit patients with Eisenmenger syndrome7 and likely will benefit other patients with PAH in CHD.⁸ Endothelin-receptor antagonist (ERA) therapy, specifically with bosentan, has been shown to improve objective measures as well as quality of life in patients with Eisenmenger syndrome, but its effect on mortality is less well known.⁹ It is for this reason that patients with Eisenmenger syndrome, specifically those with reduced exercise capacity, are started on a treatment with ERA monotherapy then increased to combination therapy if needed (Class IIa recommendation). Phosphodiesterase type 5 inhibitors, like ERAs, have shown favorable functional and hemodynamic results in this patient group. There are less data on the latest-generation PAH therapies such as macitentan, selexipag, and riociguat in this patient group. Most treatment centers use a symptom-oriented treatment strategy, starting with an oral ERA or phosphodiesterase type 5 inhibitor in low- to intermediate-risk patients and then escalating therapy if symptoms persist or there is clinical deterioration (Class Ia recommendation). However, it must be remembered that most patients with PAH in CHD, including patients with Eisenmenger syndrome, are generally considered moderate- to high-risk patients⁵ and may require treatment with combination therapy and possible use of parenteral prostacyclins (Class Ia recommendation).
7. If parenteral prostacyclin therapy is warranted, it should be started as soon as possible because these medications work best when started early.¹⁰ Rarely, patients with closed or coincidental defects who meet strict criteria for vasodilator responsiveness, defined as a decrease of mean PAP of 10 mmHg or greater and below 40 mmHg acutely with inhaled nitric oxide, can be treated with calcium channel blocker therapy only.
8. Heart-lung transplantation or lung transplantation with heart surgery is an option in rare patients who are unresponsive to medical treatment, but it must be evaluated on a case-by-case basis because surgical complexity and organ availability are both limiting.

References

1. Baumgartner H, De Backer J, Babu-Narayan SV, et al. 2020 ESC Guidelines for the management of adult congenital heart disease. Eur Heart J 2021;42:563-645.
2. van der Linde D, Konings EE, Slager MA, et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 2011;58:2241-7.
3. Marelli AJ, Ionescu-Ittu R, Mackie AS, Guo L, Dendukuri N, Kaouache M. Lifetime prevalence of congenital heart disease in the general population from 2000 to 2010. Circulation 2014;130:749-56.
4. Engelfriet PM, Duffels MG, Möller T, et al. Pulmonary arterial hypertension in adults born with a heart septal defect: the Euro Heart Survey on adult congenital heart disease. Heart 2007;93:682-7.
5. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37:67-119.
6. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019;53:1801913.
7. Dimopoulos K, Inuzuka R, Goletto S, et al. Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension. Circulation 2010;121:20-5.
8. Galiè N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394-403.
9. Galiè N, Beghetti M, Gatzoulis MA, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 2006;114:48-54.
10. Skoro-Sajer N, Gerges C, Balint OH, et al. Subcutaneous treprostinil in congenital heart disease-related pulmonary arterial hypertension. Heart 2018;104:1195-9.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Cardiovascular Care Team, Congenital Heart Disease and Pediatric Cardiology, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Valvular Heart Disease, Vascular Medicine, Implantable Devices, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and CHD and Pediatrics, Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Imaging, CHD and Pediatrics and Interventions, CHD and Pediatrics and Prevention, Lipid Metabolism, Heart Transplant, Pulmonary Hypertension, Interventions and Imaging, Interventions and Structural Heart Disease, Interventions and Vascular Medicine, Echocardiography/Ultrasound, Magnetic Resonance Imaging, Hypertension

Keywords: ESC Congress, ESC20, Phosphodiesterase 5 Inhibitors, Epoprostenol, Platelet Aggregation Inhibitors, Quality of Life, Nitric Oxide, Calcium Channel Blockers, Hypertension, Pulmonary, Eisenmenger Complex, Pulmonary Artery, Thoracic Surgery, Prostaglandins I, Heart-Lung Transplantation, Vasodilator Agents, Mitral Valve Stenosis, Alagille Syndrome, Atrial Pressure, Pulmonary Medicine, Phlebotomy, Phlebotomy, Blood Vessel Prosthesis, Polycythemia, Neonatology, Anesthesiology, HIV Infections, Anemia, Iron-Deficiency, Exercise Tolerance, Genetics, Medical, Genes, Modifier, Pulmonary Valve Stenosis, Vascular Resistance, Cardiac Catheterization, Anticoagulants, Echocardiography, Magnetic Resonance Imaging, Oximetry, Arrhythmias, Cardiac, Tomography, Physical Examination, World Health Organization, Vaccination, Endothelin Receptor Antagonists, Patient Care Team, Oxygen Inhalation Therapy, Heart Valves, Family Characteristics, Vitamin K

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