Pulmonary hypertension in adults with congenital heart defects (ACHDs)—in light of the 2022 ESC PAH guidelines—part I: definition, epidemiology, classification, diagnostics, genetics, risk stratification and follow-up, gender aspects

Introduction

Congenital heart defects (CHDs) are the most common isolated congenital organ anomaly. Worldwide, approximately 1.5 million children are born with CHD per year, in Germany approximately 8,500 (1,2). Due to improved medical care in the industrialized world, more than 95% of them reach adulthood. Worldwide, there are currently about 50 million adults living with congenital heart diseases (ACHDs), in Germany about 360,000 (3,4). One of the most important complications of CHD is pulmonary hypertension (PH) or pulmonary vascular disease (PVD), which can develop at any age (5).

The European Society of Cardiology (ESC) and the European Respiratory Society (ERS) 2022 revised the 2015 ESC and ERS guidelines. They include the hemodynamic definition of PH clinical classification, diagnostic strategies, risk assessment, risk-stratified therapy, specifics of left heart, pulmonary disease, hypoxia, chronic thromboembolic PH (CTEPH), and their care by a multidisciplinary team working with patient associations and engaging in research, teaching, and education (6,7). Because little space is given to PH in ACHDs in this context, the present article aims to provide important additional information on this constellation of problems (8-10).

Definition of pulmonary arterial hypertension (PAH)

The definition of PH and its various forms is based on hemodynamic parameters obtained by cardiac catheterization at rest and in the supine position. Although hemodynamics represent the central element for characterizing PH, the definitive diagnosis and classification of PH should reflect the entire clinical context and take into account the results of all examinations.

PH is defined by a mean pulmonary arterial pressure (mPAP) >20 mmHg at rest (Table 1), according to the 2022 ESC/ERS guidelines.

In precapillary PH, it is important to include pulmonary vascular resistance (PVR) and pulmonary arterial wedge pressure (PAWP) in the definition to distinguish increased pulmonary arterial pressure (PAP) due to PVD from increased PAP due to left heart disease (LHD), and from increased pulmonary blood flow (Table 1).

Based on the available data, the upper limit of normal PVR and the lowest prognostically relevant threshold of PVR were set at ~2 Wood units (WU) (11-14). PVR relates to body surface area and age, and higher PVR values may exist in healthy elderly individuals.

Of particular note in the current ERS/ESC-PH guideline, especially for adults with shunt lesions in the setting of CHD, is the definition of “unclassified PH”: there are patients with elevated mPAP (>20 mmHg) but low PVR (≤2 WU) and low PAWP (≤15 mmHg). These patients are often characterized by increased pulmonary blood flow and, although they have PH, do not meet the criteria for pre- or postcapillary PH. In this case, “unclassified PH” is present according to the current ESC/ERS guideline.

Patients with increased pulmonary blood flow due to shunt vitium in CHD may fall under this definition.

Epidemiology and classification of PAH

PH is an important health problem with a worldwide PH prevalence of approximately 1% (9,15). Of adults with CHD, approximately 3–7% develop PAH during their lifetime, especially women. The incidence depends largely on the type of underlying CHD and increases with patient age and age at defect closure (16). After correction of a simple heart defect, the estimated PAH prevalence is 3% (17). Eisenmenger syndrome, the most severe form of PAH in CHD, is decreasing in industrialized countries. While fewer patients with simple CHD treated early will develop PAH in adulthood in the future, more patients with PAH in complex CHD are expected to develop PAH in adulthood and those who continue to develop PAH decades after defect closure (18). In addition, patients who develop PH because of concomitant cardiac and noncardiac diseases, e.g., LHD or chronic obstructive pulmonary disease (COPD), portal hypertension infectious diseases [schistosomiasis, human immunodeficiency virus (HIV)], and living at high altitudes (15).

Also in the current 2022 ESC guidelines, the PH classification is based on the proposals of the previous World Conferences or World Symposia. The assignment of patients to this classification is therapeutically important (7,9) (Table 2). Patients with PH in CHD appear in this classification preferably in groups 1 and 2. However, it must be noted that adults with CHD are then also assigned to classes 3, 4, and 5 with increasing age depending on comorbidities (19).

Specific changes in the new classification include the subdivision of idiopathic PAH (IPAH) group 1.1 into the subgroups non-vasoreactivity responders (group 1.1.1) and vasoreactivity responders (group 1.1.2), the reclassification of PH patients with additional features of venous [pulmonary venoocclusive disease (PVOD)] or capillary [pulmonary capillary hemangiomatosis (PCH)] disease into group 1.5, the subdivision of IPAH patients into IPAH patients without comorbidities and IPAH patients with cardiopulmonary comorbidities, and the restructuring of group 5 (20).

PAH associated with congenital shunt lesion is classified into four clinically and prognostically significant groups: Eisenmenger syndrome, correctable or noncorrectable left-to-right shunts, incidental PAH associated with an CHD, and PAH after reparative treatment (Table 3).

For everyday clinical practice, the classifications given in the 2022-ESC guideline appear to be sufficient, but in many cases do only limited justice to the complexity of the clinical pictures. A classification according to severity or complexity of CHD does not exist, although complex CHD, in particular univentricular hearts after modified Fontan operation, will become the focus of attention in the future due to their pulmonary vascular involvement (21).

Diagnosis of PAH—general [clinic, laboratory, electrocardiogram (ECG), lung function, spiroergometry, X-ray, magnetic resonance imaging (MRI), computed tomography (CT), ventilation/perfusion (V/Q) scintigraphy]

General

The diagnostic algorithm is used to confirm the diagnosis and clarify PAH, especially to exclude or confirm LHD (group 2 PH) or structural lung disease (group 3 PH).

Clinic

Clinical symptoms are usually attributable to insufficiency of the right ventricle (RV) (22,23). Exertional dyspnea is the most common symptom in adults (24,25).

Laboratory chemical tests

The recommended laboratory chemistry tests at initial diagnosis are given in Table 4.

ECG

A rightward shift of the cardiac electrical axis on ECG has a high predictive diagnostic value for PH (26). However, a normal ECG does not exclude PH.

With a normal ECG in combination with unremarkable cardiac stress markers [B-type natriuretic peptide (BNP)/N-terminal prohormone BNP (NT-proBNP)], there is little likelihood of PH even with increased risk of PH (27,28) (Table 5).

Pulmonary function diagnostics and arterial blood gases

Spirometry is normal or only mildly restrictive and/or obstructive altered, higher grade abnormalities are occasionally found in PH-CHD and in group 3 PH (29,30). Lung diffusing capacity for carbon monoxide (DLCO) is normal or mildly reduced (29). Arterial partial pressure of oxygen (PaO₂) is normal or slightly reduced; if severely reduced, right-to-left shunt is suspected, among others. Arterial partial pressure of carbon dioxide (PaCO₂) is typically lower than normal due to alveolar hyperventilation and prognostically relevant (31,32). An elevated PaCO₂ is highly unusual and reflects alveolar hypoventilation, which per se may be causative or driving PH. Polysomnography is indicated to rule out ventilatory dysfunction (33).

Spiroergometric examination

Spiroergometry shows a typical picture with low end-tidal partial pressure for carbon dioxide (PETCO₂), high ventilatory equivalent for carbon dioxide, decreased oxygen pulse [VO₂/heart rate (HR)], and decreased maximal oxygen uptake (peak VO₂) (34).

X-ray thorax

A normal X-ray does not exclude PH (35). Typically, there is enlargement of the right heart and pulmonary artery, with so-called ‘pruning’ when severe, indicating rarefaction of the peripheral pulmonary arteries (Table 6) (22-24,36,37).

Cardiac MRI (cMRI)

RV volume, right ventricular ejection fraction (RVEF) and stroke volume (SV) are considered essential factors for the prognostic assessment of PH using cMRI (15,22,23,38-42).

Non-contrast and contrast-enhanced thoracic CT examinations and digital subtraction angiography

An enlarged PA diameter, a PA to aorta ratio of 0.9, and enlarged RVs are typical findings on CT (35). A PA diameter ≥30 mm, right ventricular outflow tract (RVOT) wall thickness ≥6 mm, and septal deviation ≥140° (or RV:LV ratio ≥1) is highly predictive of PH (43).

The accuracy of contrast CT pulmonary angiography (CTPA) for CTEPH is limited but can be increased using high-quality multidetector CT scanners and interpretation by experienced investigators (44).

V/Q lung scan (scintigraphy)

A V/Q lung scan is recommended to rule out CTEPH (45,46). In the absence of parenchymal lung disease, a normal perfusion scan excludes CTEPH with a negative predictive value of 98% (47,48). Perfusion defects with V/Q mismatch, however, may occur in 7–10% of patients with PVOD/PCH or PAH (49,50). The presence of contrast in extrapulmonary organs may indicate cardiac or intrapulmonary right-to-left shunt (35).

Abdomen ultrasound

To exclude portal hypertension and in progressive disease with increasing right ventricular dysfunction, an end-organ damage assessment should be performed (51).

Diagnostics of PAH—genetic counseling and testing

Mutations in PAH genes have been identified in familial PAH, IPAH, PVOD/PCH, and anorexigen-associated PAH [Tab. 13 in the ESC-guideline (52)]. All patients with the above forms of PAH should be informed of the risk of genetic disease and that family members may carry a mutation that increases the risk of PAH, allowing screening and early diagnosis (52,53).

Genetic counseling by appropriately trained PAH specialists (in Germany, for example, with the qualification “Fachgebundene Genetische Beratung”) or human geneticists should be performed prior to genetic testing. For asymptomatic family members, this is obligatory in Germany (52).

If the familial mutation is known and an unaffected family member test negative for the mutation, the risk of PAH for that person is the same as for the general population (52).

Tab. 13 in the ESC-guideline (52) summarizes clinical findings that may occur in the context of the above mutations and recommended investigations.

A thorough history and examination is essential, as mild findings may be overlooked.

As more genes associated with PAH are discovered, it becomes more difficult to test them individually. Next-generation sequencing (NGS) has enabled the development of gene panels to examine multiple genes simultaneously (41). However, it is important to verify the genes included in the panel at the time of testing because the composition of gene panels changes as science advances.

Commentary related to ACHDs

It has been shown several times that ACHDs may also have PAH-causing mutations. Therefore, in addition to hereditary PAH, IPAH, PVOD/PCH, and anorexigen-associated PAH, CHD-associated PAH (CHD-APAH) is also listed in the original publication to which the guidelines refer for the explicitly named group of PAH forms with known genetic predisposition (52).

While Table 7 refers to CHD-APAH only in the gene SOX17, notably mutations in the TBX4 and BMPR2 genes were also identified in this patient population (54). To date, it is unclear whether mutations may be present in all forms of CHD-APAH.

Especially in patients with simple heart defects [atrial septal defect (ASD), ventricular septal defect (VSD), patent ductus arteriosus (PDA), patent foramen ovale (PFO)], a genetic predisposition has been demonstrated so far (55,56).

Initial data from SOX17 mutation carriers with CHD suggest that, similar to what has been described for BMPR2 mutation carriers, genetic predisposition may also affect earlier age at diagnosis and associated poorer prognosis in CHD-APAH patients (53).

Particularly noteworthy are chromosome 22q11 deletion syndrome and pulmonary atresia with VSD (PA/VSD) and major aortopulmonary collateral arteries (MAPCAs). The associated PH is very specific and usually does not respond well to targeted PH medication.

Moreover, it is important to recognize that Down syndrome persons with Down syndrome have an increased incidence of PH, often associated with CHD or persistent PH of the newborn (PPHN) and other respiratory comorbidities. The different underlying causes and risk factors for PH require a multidisciplinary treatment approach to these patients.

Although only very few studies address PH-targeted pharmacotherapie in this population, endothelin receptor antagonists (ERA) can improve quality of life, exercise capacity, and functional classification.

Diagnostics of PAH—echocardiography

Among patients with suspected PAH, transthoracic echocardiography (TTE) is used as the most important noninvasive test for assessment of pulmonary vascular hemodynamics and initial estimation of right atrium (RA), RV, and pulmonary trunk pressures in CHD patients. The echocardiographic criteria for PAH assessment listed in the 2022 ESC/ERS guideline on the diagnosis and management of PH must be critically applied in CHD (9). Anatomic-hemodynamic features such as shunts or stenoses in the heart or downstream pulmonary pathway must be taken into account to correctly classify echocardiographically obtained parameters and to identify abnormalities favoring secondary PAH (shunt lesions, etc.).

Echocardiographic PAH assessment in complex anomalies such as CHD with collateral supply to the lung, segmental PAH, or pulmonary vasculopathy with Fontan circulation in a functionally univentricular heart is severely limited.

The following are examples of common echocardiographic parameters used for PAH assessment and specifics for use in CHD.

Diagnosis of PAH—invasive examination (cardiac catheterization and testing)

Important goals of cardiac catheterization examination are:

• Determination of the severity of PH;
• Differentiation of flow-related, pulmonary vascular, and postcapillary components;
• Identification of possible causes of group 3 and 4 PH;
• Identification of patients with heart defects who are still operable.

In general, venous and arterial catheterization should be performed according to a standardized protocol in cases of shunt lesions. In ACHDs >40 years or a risk constellation for coronary artery disease, coronary angiography should be performed in addition. In ACHDs with PAH, a left heart problem may aggravate the PAH. LHD may lead to elevated left atrial pressure, which may be associated with subsequent pulmonary vascular remodelling, vasoconstriction, and an increase in PVR. This has to be determined during invasive diagnostics.

A vasoreactivity test may be helpful in patients with PAH in shunt lesion (ASD, VSD, PDA) with hemodynamically relevant left-to-right shunt and a PVR >3 WU in conjunction with other clinical, laboratory, and imaging findings, to clarify the possibility of defect occlusion (see Table 8) (57). However, there are no prospective studies that can reliably predict how PVR in PAH-CHD will develop under treatment in the absence of reactivity in the acute test.

Risk stratification and follow-up

For ACHDs, detailed suggestions for specific risk stratification do not exist in the 2022-ESC guidelines either. The risk stratification using 3- or 4-strata from the guideline cannot be readily adopted for PAH-CHD patients. However, the common parameters are also applied in these patients: WHO functional class, exercise limitation on 6-minute walking distance (6MWD) or ergospirometry, hospitalizations for cardiac events, rhythm profile, pulse oximetry, biomarkers (including NT-proBNP, C-reactive protein, iron metabolism parameters, serum creatinine, serum uric acid, serum albumin, oxygen saturation), and RV function parameters of echocardiography or MRI.

Cardiac catheterization in ACHDs with PAH is complex and not without risk. It is usually not routinely repeated and thus is not a suitable parameter for follow-up observations. Re-catheterization is more likely to occur in cases of diagnostic ambiguity or clinically relevant changes.

Especially for adults with larger shunts or an Eisenmenger reaction, there is a lack of adaptation of the risk criteria or the target criteria for PAH-specific medication, as these patients differ from the other PAH groups in terms of severity, stability, and prognosis of the disease.

Criteria for operability of PAH patients who have not yet developed Eisenmenger syndrome have been defined by various expert panels but are inconsistent. Especially in this patient group, it is difficult to identify predictors that allow or prohibit shunt closure.

The following criteria could serve as therapeutic targets in PAH-CHD: stabilization or improvement in functional class and clinical findings, stable stress test, stable or improved serum BNP levels a stable or improved RV function (on echo or MRI), in individual cases, stable or improved hemodynamics.

The follow-up plan for PAH-CHD is largely consistent with the general recommendations of the ESC/ERS guidelines and includes history, functional class, clinical examination, ECG and long-term ECG, 6-minute walk test, spiroergometry [cardiopulmonary exercise test (CPET)], echocardiography, and laboratory investigations.

Risk stratification and follow-up in special situations (e.g., syndromes, trisomy 21, …)

Approximately 15% of heart defects are syndromically associated (58). Trisomy 21, the most common chromosomal aberration worldwide with approximately 1 in 800 births (59), is associated with CHDs in approximately 40–50% of cases. Atrioventricular septal defect is the most common, followed by VSD, less commonly isolated ASD of the secondary type, and isolated persistent ductus arteriosus (60,61). In uncorrected shunts, irreversibly fixed PH with shunt reversal may develop early and may lead to significantly shortened survival (62,63). Approximately one-third of all patients with Eisenmenger’s reaction have trisomy 21. There is also an increased incidence of PH in individuals with trisomy 21, due to additional genetic, congenital, and environmental factors (64). Even initially, there is an increased risk for the occurrence of PPHN (65) and PH occurring later in life, with an incidence of 1.2–5.2% (65-67), the lifetime prevalence is not known (68). Affected individuals often fall into multiple PH classification categories, which complicates risk stratification and guideline-based therapy (69). An individualized approach, including invasive hemodynamic evaluation if necessary, by pediatric cardiologists and adult cardiologists with ACHDs certification and expertise in PH is therefore required.

Gender aspects

Although precise prevalence data are not yet available, the female predisposition to PH in CHD is well known (70-72). The exact pathomechanism has not been fully elucidated to date, but a relationship with hormonal balance, is discussed. Currently, sex hormones are thought to lead to a higher prevalence of PAH in women even with shunt lesion (71).

Data from the Dutch CONCOR registry show that women with CHD have a 33% higher risk of developing PAH compared with men (72). In this context, the gender-specific frequency of CHD also plays an important role in the female predominance of PAH. Men tend to have more complex CHD (73,74) and have a higher prevalence of disease with aortic involvement (70,75). In contrast, in women, a higher incidence (male-to-female ratio =0.75) has been observed in recent years (76) of simple shunt defects (ASD, VSD, and atrioventricular septal defect), which in turn are more frequently associated with PAH (77).

Future research is particularly needed regarding gender-specific treatment strategies, taking into account sociocultural sex (“gender”) (74,78), as this may also have a relevant impact on manifestation, epidemiology, and pathophysiology (79). Because gender differences are a nonmodifiable risk factor, explicit inclusion in the guideline seems essential.

Conclusions

Comprehensive data and controlled studies on the management of PAH in patients with CHD (PAH-CHD) are limited. Existing studies typically involve a small number of patients with simple shunt lesions that have undergone defect closure, while more complex CHD cases are rarely included. Consequently, it remains uncertain which patients truly benefit from targeted PAH therapies.

Given this gap in research, it is crucial to establish clear recommendations and guidelines for effective patient management and advice on the classification of PAH, diagnostic assessments, genetic counseling, gender considerations, risk stratification, and appropriate follow-up procedures.

Moreover, it is essential to expand specialized care for ACHDs and PAH. This care should be delivered by experts in specialized clinics and practices, in collaboration with patient associations, to ensure that affected individuals receive the necessary attention and support.

Acknowledgments

The first author extends his sincere gratitude for all the invaluable support of research and practice in the field of congenital cardiology, particulary to the Deutsche Herzstiftung e.V., Deutsche Rentenversicherung-Rheinland, Herzkind e.V., and the Gesellschaft für Prävention e.V. (GPeV), the Manfred-Roth-Stiftung and the Dr. Axe-Stiftung.

Funding: This work was funded in part by “Janssen-Cilag GmbH”.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Cardiovascular Diagnosis and Therapy for the series “Current Management Aspects of Adult Congenital Heart Disease (ACHD): Part VI”. The article has undergone external peer review.

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-148/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-148/coif). The series “Current Management Aspects of Adult Congenital Heart Disease (ACHD): Part VI” was commissioned by the editorial office without any funding or sponsorship. H.K. served as the unpaid Guest Editor of the series. H.K. received sponsorship and honoraria from Janssen/Jonson&Johnson, and Bristol Myers Squibb, and participated in the steering board of COMPERA International. G.P.D. has received honoraria and consulting fees from Janssen Pharmaceuticals. I.D. serves as an unpaid board member for Treasurer of the German Society for Pediatric Cardiology and Congenital Heart Disease. S.A. serves as board member for European Society of Cardiology, and Deutsche Herzstiftung. C.A.E. received honoraria for lectures and presentations from OMT and MSD, consulting fees from MSD. C.A.E. is co-inventor of the issued European patent “Gene panel specific for pulmonary hypertension and its uses” (EP3507380). E.G. has received research grants outside the submitted work from Actelion, Janssen, Bayer, MSD, Merck, Ferrer; research grants to the institution outside the submitted work from Acceleron, Actelion, Bayer, MSD, Janssen, Liquidia, United Therapeutics, OMT; consultancy fees outside the submitted work from Actelion, Janssen, Bayer, MSD, Merck, Ferrer; Speaker honoraria outside the submitted work from Actelion, Bayer/MSD, GSK, AOP, Janssen, phev, OMT, GEBRO, Ferrer, GWT; participation in AdBoards from MSD and Ferrer; unpaid board member for A DUE Steering committee and patient organisation phev. M.H. received consulting fees, honoraria, and travel support from Janssen. S.M. received Research Grant from German Center for Lung Research (DZL). A.U. received consulting fees from Medtronic. U.H. serves as an unpaid board member for Deutsche Gesellschaft für Kinderkardiologie und Angeborene Herzfehler, and Deutsche Gesellschaft für Kinder- und Jugendmedizin. C.A. received lecture and consulting fees from Janssen. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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