2023 AHA科学声明：先天性心脏病的肺动脉高压

CLASSIFICATION OF PH ASSOCIATED WITH CONGENITAL HEART DISEASE

The classification of PH has evolved to reflect the congenital cardiac lesions important in pediatric PH. 5,6 The updated classification, from the 6th WSPH in 2018, modified both the definition of PH and the characterization of PH–congenital heart disease in patients with biventricular and single-ventricle circulations. 1,2,7 Four WSPH pathogenetic groups include forms of PH–congenital heart disease: group 1, PAH; group 2, PH due to left heart disease; group 4, PH with pulmonary artery obstructions; and group 5, PH with unclear or multifactorial mechanisms, including complex congenital heart disease (Figure). Each time the classification has been updated, there has been increased recognition of the fact that congenital heart disease is complex and cannot fit neatly into 1 group. Thus, although the 6th WSPH has taken a great leap in addressing this, future classifications may include recognition that patients can fit into ${>}1$ WSPH group and that individualized management is vital. Patients may be in 1 group and over time may develop characteristics of a different group in the classification compared with their initial presentation. Further descriptions and diagnostic criteria for PH–congenital heart disease are included in Table2.

Group 1 PAH includes associated PAH–congenital heart disease, with mean pulmonary artery pressure ${\tt>}20\$ mmHg, pulmonary capillary wedge pressures ≤ 15 mmHg, and indexed PVR (PVRi) ${\geq}3$ WU∙m 2 (mmHg/L/min/m2). The pathophysiology of PAH–congenital heart disease is variable and complex, affecting management decisions. 8 In patients with large shunts, pulmonary vascular disease develops secondary to shear stress, endothelial damage, smooth muscle proliferation, remodeling of the vasculature, and ultimately obliteration of the microvasculature, similar to idiopathic PAH (IPAH). 2 Pulmonary vasoconstriction is related to endothelial dysfunction, resulting in an imbalance between vasodilators, for example, nitric oxide and prostacyclin, and vasoconstrictors, including endothelin-1, vascular endothelial growth factor, serotonin, and cytokines. At the cellular level, the endothelium, smooth muscle cells, fibroblasts, inflammatory cells, circulating progenitor endothelial cells, and platelets all contribute to vascular remodeling. 9–11 Awareness of the role of genetic factors in PAH–congenital heart disease is increasing, with a number of genes being reported, including BMPR2 , SOX17 , TBX4 , and other rare inherited variants of NOTCH1 , PTPN1 , and RAF1 , as well as other genes with de novo variants. 12,13 PAH–congenital heart disease (group 1.4.4) occurs in left-to-right shunt lesions with 4 described clinical and hemodynamic profiles:

1. Eisenmenger syndrome (ES) is clinically defined as unrepaired, unrestrictive congenital heart disease in which severe elevation in PVR develops, resulting in reversal of shunt direction from systemic to

 Figure. Different subgroups of pulmonary hypertension in congenital heart disease. HD indicates heart disease; and PAH, pulmonary arterial hypertension.

pulmonary to predominantly pulmonary to systemic. The hallmark of ES is cyanosis with consequences of chronic hypoxemia, including secondary erythrocytosis and multisystem involvement. 14

2. Unrepaired moderate to large defects with mildly to moderately elevated PVR with predominantly left-to-right shunt form the second subgroup of PAH–congenital heart disease. This group has considerable heterogeneity in outcome, depending on the severity and reversibility of vascular remodeling. 6 Criteria for operability incorporating baseline hemodynamics and response to acute vasodilator testing have been proposed (Table2). 15,16 Patients can be divided into those in whom congenital heart disease is still possibly repairable (PVR < 4 WU∙m 2 ) and those in whom congenital heart disease is

likely not repairable with physiology closer to Eisenmenger physiology (when PVR ${>}8$ WU∙m 2 ). 2 A third group has an intermediate status (PVR, 4–8 WU∙m 2 ) and should be considered for targeted PH therapy with re-evaluation for operability on an individual basis. 2 Individual clinical characteristics, including age, shunt location, associated diagnoses, and saturations, must be considered when determining appropriateness for intervention.

3. PAH with coincidental congenital heart disease includes the subset of patients with small pretricuspid or posttricuspid shunts associated with PAH. These defects are considered coincidental and not causative of the degree of PAH. These patients have a clinical course and poor survival, similar to patients with IPAH. 2,17,18

Table 2. PH Associated With Congenital Heart Disease

|PH group|Description|Hemodynamic criteria|Examples| Treatment/manage- ment considerations/ gaps | |---|---|---|---|---| |Group 1||||| | PAH-congenital heart disease | PAH associated with intracardiac and extracardiac shunt lesions | mPAP >20 mm Hg PCWP or LAP ≤15 mm Hg PVR ≥3 WU-m2 | Pretricuspid shunt ASD Partial AVSD PAPVR TAPVR Posttricuspid shunt VSD AVSD with large ventricular component PDA Aortopulmonary window Other TGA Common arterial trunk |111| | PAH-congenital heart disease | ES Reversal from systemic-to-pulmonary shunt to bidirectional or reversed shunt | PVR≥SVR PVR generally>10 WU-m2 Op | Pretricuspid shunt ASD Partial AVSD PAPVR TAPVR Posttricuspid shunt VSD AVSD with large ventricular component PDA Aortopulmonary window Other TGA Common arterial trunk |111| | PAH-congenital heart disease | Unrepaired congenital heart disease with prevalent left-to-right shunt Repairable* Possibly repairablegray zone6 Unrepairable |PVR | Pretricuspid shunt ASD Partial AVSD PAPVR TAPVR Posttricuspid shunt VSD AVSD with large ventricular component PDA Aortopulmonary window Other TGA Common arterial trunk ||

AS indicates aortic stenosis; ASD, atrial septal defect; AVSD, atrioventricular septal defect; DPG, diastolic pressure gradient; ES, Eisenmenger syndrome; IPAH, idiopathic pulmonary arterial hypertension; LA, left atrium; LAP, left atrial pressure; LVEDP, left ventricular end-diastolic pressure; MAPCA, major aortopulmonary collateral artery; mPAP, mean pulmonary artery pressure; PA, pulmonary atresia; PAH, pulmonary arterial hypertension; PAPVR, partial anomalous pulmonary venous return; PCWP, pulmonary capillary wedge pressure; PDA, patent ductus arteriosus; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; PVS, pulmonary vein stenosis; Qp, pulmonary flow; Qs, systemic flow; Rp, pulmonary resistance; Rs, systemic resistance; SVR, systemic vascular resistance; TAPVR, total anomalous pulmonary venous return; TPG, transpulmonary gradient; TGA, transposition of the great arteries; VSD, ventricular septal defect; and WU, Wood unit.

\*Operability criteria based on expert opinion incorporating patient age, type of defect, comorbidities, baseline, and exertional saturations without definitive evidence for treat-and-repair strategy.

4. Persistent or recurrent PAH after surgical repair of congenital heart disease is associated with poor prognosis. 2,17,18 To date, there are no sufficiently reliable data to predict which patients will fall into

this category. Although there are data on the use of vasoreactivity testing to determine operability, these studies have not been proven sufficiently reliable. 17,18

In group 2 PH, left-sided heart disease is increasingly recognized as a cause of PH in congenital heart disease and may progressively develop over time. 19 It occurs in the setting of elevated pulmonary venous pressure, resulting in a proportional elevation of precapillary pulmonary artery pressure (isolated postcapillary PH) or PH in excess of the pulmonary venous hypertension with associated pulmonary vascular disease (PVR ≥ 3 WU∙m 2 ), referred to as combined precapillary and postcapillary PH. 1 Congenital cardiac lesions that belong to WSPH group 2.4 include those that directly obstruct pulmonary venous or left atrial flow and those that indirectly result in left atrial hypertension due to elevated left ventricular filling pressures (Table2). 2

Group 4.2.5 PH has been classified in the 6th WSPH classification as a subgroup of PH due to pulmonary artery obstructions. However, this rare subgroup of pediatric patients has not been evaluated for the presence of distal pulmonary vascular disease (as may be seen in chronic thromboembolic PH), and their response to targeted therapy has not been studied (Table2).

Group 5.4 PH includes PH with unclear or multifactorial mechanisms such as single-ventricle physiology, segmental PH, and scimitar syndrome (Table2). 2

1. Functional single-ventricle circulation encompasses anatomical defects with an effective single ventricular pump driving both systemic and pulmonary circulations. Staged palliation, culminating in the Fontan repair, directs caval return directly to the pulmonary arteries, resulting in passive, nonpulsatile pulmonary blood flow requiring an unobstructed pathway with low PVR. Patients with nonpulsatile cavopulmonary flow can develop microvascular remodeling that results in a failed Fontan state, which affects survival. 20 The PH diagnostic definition of mean pulmonary artery pressure ≥ 20 mmHg is irrelevant in the Fontan circulation; instead, pulmonary hypertensive vascular disease for univentricular circulations is defined as a mean transpulmonary gradient ${>}6$ mmHg and an PVRi ${\tt>}3$ WU∙m 2 . 21,22 Measurement of PVR is challenging in this group because of additional sources of pulmonary blood flow, residual antegrade pulmonary flow, segmental pulmonary arterial stenoses, and flow across the Fontan fenestrations.

2. Segmental PH occurs when different lung segments develop varying degrees of pulmonary hypertensive vascular disease, with at least 1 segment of pulmonary vasculature remaining nonhypertensive. 23 There is often an aortic source of pulmonary blood flow to a portion of the lungs, as well as the presence of segmental branch pulmonary artery stenosis or the presence of segmental branch pulmonary artery stenosis, either alone or in combination with other congenital heart defects.

3. Scimitar syndrome is a distinct form of partial anomalous pulmonary venous drainage of right pulmonary veins to the inferior vena cava with associated right lung hypoplasia and anomalous systemic arterial supply to a portion of the right lung. PH can develop as a result of variable mechanisms, including associated congenital heart disease, excessive pulmonary blood flow, systemic arterial supply of pulmonary segments, obstructed pulmonary veins, or their combination. 24 Presentation in infancy with pulmonary hypertensive vascular disease portends a worse prognosis. 25

It is important to recognize that many pediatric patients may have multiple reasons for PH and simultaneously have features of different PH groups, as seen in patients with Down syndrome with PAH–congenital heart disease. Down syndrome is associated with lung hypoplasia and alveolar simplification, which is complicated by other comorbidities such as congenital heart disease, persistent PH of the newborn, thyroid disease, sleep-disordered breathing, and prematurity, and other vascular disorders such as Moyamoya disease are common cotravelers. 26,27 Biomarkers such as NT-proBNP (N-terminal pro-B-type natriuretic peptide) and galectin-3 may help distinguish between children with Down syndrome with and those without PH. 28 Genetic abnormalities in children may predispose to antiangiogenesis ( COL18a1 [endostatin]), a proinflammatory state ( IFNAR1/2 [interferon $\upalpha/upbeta$ receptors 1 and 2]), and lung disease, all contributing to PH. 27 Future genetic studies will further our understanding of the role of underlying molecular pathways compared with physiologically induced mechanisms and their potential overlap, which could in turn determine potential responses to therapies and thus lead to even further modifications of classifications.

SCREENING AND DIAGNOSING PH– CONGENITAL HEART DISEASE

Clinical Presentation and Initial Testing

Symptoms of PH in children are frequently subtle and may delay the diagnosis of PAH–congenital heart disease. In infants, poor feeding, tachypnea, tachycardia, and poor growth are common. Syncope is rare in ES, but shortness of breath is common. 29 Physical signs may include a loud split second heart sound, gallop, and holosystolic murmur of tricuspid regurgitation. Edema of the face, hands, ankles, and hepatomegaly is a later sign of right-sided heart failure. 30 Chest radiographs may provide clues to the degree of shunting in children with associated PAH– congenital heart disease. Congested vasculature is often seen in large left-to-right intracardiac shunts. Oligemia may be present in patients with restricted blood flow such as those with ES. However, radiographic findings

do not always correlate with disease severity. Evidence of right ventricular (RV) hypertrophy on ECG is present in most children with PH. Some studies have suggested that the specificity $(69\%)$ and positive predictive value $(67\%)$ of ECG are low in children with a diagnosis of PH by echocardiography. 31 In a study of 456 children in the TOPP registry (Tracking Outcomes and Practice in Paediatric Pulmonary Hypertension) with catheterizationproven PH, no child with PH had a normal chest x-ray, ECG, and echocardiogram. 32

Transthoracic Echocardiography

Transthoracic echocardiography is the first-line cardiovascular imaging modality for the diagnosis of PH. It is the most accessible noninvasive tool used for routine assessment 33–40 and for serial follow-up of PH associated with congenital heart disease. 41,42 Developments in echocardiography have led to new insights into the structure and function of the RV and its role in PH. 43,44 Conventional echocardiography-based imaging includes assessment of anatomy in 2 dimensions, hemodynamics through Doppler echocardiography, and qualitative and quantitative evaluation of RV and left ventricular function. 35–37,41,45–47 Advanced echocardiography includes evaluation of right-sided heart size and function, myocardial mechanics, and estimated ratio of RV to pulmonary arterial coupling. 48–56 Table3 shows the advantages and limitations of each of echocardiographic techniques used in pediatric PH. Different echocardiography parameters have been found in small studies to be useful in identifying high-risk patients who are likely to develop adverse clinical outcomes. 51,61,67,69,70 Table 4 demonstrates the echocardiographic views needed to obtain the qualitative and quantitative parameters in pediatric PH associated with congenital heart disease.

Cross-Sectional Imaging

Advancements in magnetic resonance imaging and computed tomography have allowed high-resolution evaluation and multiplanar reconstruction capabilities in the diagnosis and screening of PH. Cross-sectional imaging has become pivotal in consensus statements on the care of adult and pediatric patients with PH. 75,76 Underlying cardiovascular lesions can affect the severity of PH. Thus, the ability to view structures simultaneously in all 3 dimensions makes computed tomography/magnetic resonance imaging valuable in delineating complex congenital heart disease, particularly in older patients with limited acoustic windows. Both computed tomography and magnetic resonance angiography can identify extracardiac lesions such as patent ductus arteriosus and pulmonary vein anomalies and stenoses. Hemodynamic data, direction of intracardiac shunting and degree of shunting, can be calculated from magnetic resonance imaging phase-contrast imaging. Physiological sequelae, including pulmonary artery dilation and pulmonary vascular pruning, are easily identified. Each modality has distinct

advantages and disadvantages (Table5). Patients with metallic prosthetic valves and implanted devices, including pacemakers, may not be able to undergo magnetic resonance imaging scanning because of either the presence of abandoned leads or metallic artifact obscuring vital structures of interest. Gadolinium-based magnetic resonance contrast has the rare risk of nephrogenic systemic fibrosis seen with impaired renal function. Data have emerged on concentration-dependent retention of gadolinium in brains of patients who received repeated gadolinium-based contrast. 77,78 Clinical effects in children are not yet known.

Cardiac Catheterization

Right- and left-sided heart catheterization is considered the gold standard for measuring hemodynamics in patients with congenital heart disease and advanced pulmonary vascular disease, especially to assess operability. 22,79,80 Acute vasoreactivity testing is performed at the time of catheterization and helps strategize treatment for postoperative PH. When available, inhaled nitric oxide (20–80 ppm) alone or in combination with oxygen is considered the preferred agent for vasodilator testing. 79,81–83 It is safe and short acting and offers a better pulmonary vasodilator effect than systemic agents. However, nitric oxide is not always affordable and thus is not readily available in all cardiac catheterization laboratories, particularly in low- to middleincome countries. Alternative vasodilator agents include intravenous epoprostenol, adenosine, or inhaled vasodilators such as iloprost, treprostinil, milrinone, and nitroglycerin. 84–88 Acute vasoreactivity testing is considered positive in patients with shunt lesions when there is a PVRi/indexed systemic vascular resistance (Rp/Rs) ratio ${<\!0.3}$ with an increase in pulmonary flow/systemic flow (Qp/Qs) with inhaled nitric oxide. 22,79,89 However, no prospective studies have identified reliable baseline hemodynamic or vasodilating test response cutoffs that predict reversibility after cardiac correction. Cardiac catheterization and accurate measurement of PVR can be fraught with error, as described elegantly by Viswanathan et al, 90 and the results should be carefully considered in patients with segmental perfusion abnormalities, streaming, lung disease, and airway issues, all of which may alter the hemodynamics. Duct occlusion to determine the feasibility of closure of patent ductus arteriosus and fenestration occlusion in patients with Fontan circulations are also performed to evaluate hemodynamics before intervention. Some centers use ratios of pulmonary artery to systemic artery diastolic pressure to determine operability, but no large studies are available to validate such an approach. Furthermore, cardiac catheterization and the role of acute vasoreactivity testing in persistent or recurrent PAH after repair or in patients with single-ventricle physiology are less clear and merit further evaluation.

Table 3. Echocardiographic Parameters Used at Diagnosis of PH and Follow-Up

|Echo parameters|Interpretation|Advantage|Limitations|References| |---|---|---|---|---| | Echocardiographic parameters to qualitatively assess septal position||||| | Interventricular septal flattening | Mild, moderate, or severe to indicate the severity of pulmonary hypertension | Quick visual assessments when there is not adequate TR peak velocity to estimate RVSP | Qualitative Can occur in systole and diastole, depending on pressure or volume overload Poor validation with clinically relevant measures |57,58| | End-systolic RV/ LVratio | >1 may indicate increased risk of adverse events in pediatric PH | Easy to obtain clinically| Cannot be used in patients with left- to-right shunts |59| | Eccentricity index | Eccentricity index=D2/D1 where D1=diameter 1 and D2=diameter 2 D2/D1>1.16 indicates the presence of PH | Easy to measure| Cannot be measured when the LV is obliterated |62| || Echocardiographic parameters to access hemodynamics |||| | TR peak velocity (m/s) | RVSP=SPAP= 4(TR max)2+mean RA pressure (mRAP) If TR velocity is >3m/s, PH may be suspected. | Easy to obtain| 75% of TR is measurable Modest correlation with systolic pulmonary artery pressure |60| |S/D ratio| >1.4 indicates severity of PH and increased risk of mortality |Easy to measure from TR velocity| Requires the presence of defined TR velocityin systole and diastole |61| | MeanPAP (mmHg) | mPAP=4 V(early peak pulmonary regurgitation velocity)2+RAP | Alignment of PR maybe better than TR | PR required for measurement Modest correlation with mean pulmonary artery pressure |41,45| | Diastolic PAP (mmHg) | DPAP=4 V(end-diastolic pulmonary regurgitation velocity)2+RAP | Alignment of PR maybe better than TR | PR required for measurement |41,45| |PAAT (ms)|Abnormal PAAT values with z score ||||

DPAP indicates diastolic pulmonary arterial pressure; ε A, pump function; ε E, conduit function; EF, ejection fraction; ε S, reservoir function; FAC, fractional area change; HR, heart rate; LV, left ventricular; mPAP, mean pulmonary arterial pressure; MPI, myocardial performance index; mRAP, mean right atrial pressure; PAAT, pulmonary arterial acceleration time; PAP, pulmonary arterial pressure; PH, pulmonary hypertension; RA, right atrial; RAP, right atrial pressure; RV, right ventricular; RVSP, right ventricle systolic pressure; SPAP, systolic pulmonary arterial pressure; SRS, right atrial strain rate filling; TAPSE, tricuspid annular planar systolic excursion; TDI, tissue Doppler imaging; 3D, 3-dimensional; TR, tricuspid regurgitation; 2D, 2-dimensional; and V, velocity.

Table 4. Echocardiographic Views to Obtain Hemodynamic and Functional Parameters in Patients With PH

||Echo view|Functional parameters| |---|---|---| |Doppler| Parasternal short axis | Pulmonary acceleration time/ejection time Pulmonary regurgitation early and late diastolic velocity | |Doppler|Apical 4 chamber| TR severity (none, mild, moderate, severe) TR peak velocity MPi (tricuspid tissue Doppler)71 Systolic/diastolic duration ratio from TR | ||| MPi (tricuspid tissue Doppler)71 Systolic/diastolic duration ratio from TR Doppler61 | |RA|| Tissue Doppler systolic and diastolic velocities (tricuspid, septal, mitral) | ||Apical 4 chamber|RA area, RA strain61| |R|Apical 4 chamber| Qualitative RV function (good, mildly/ moderately/severely depressed) RV end diastolic and end-systolic dimensions indexed for BSA (2D) FACpercent TAPSE with z score (M mode when available,2D) | ||| RV strain (global and segmental61,7,73 3D RV volumes and function50,51 | |L| Apical 2+4 chamber || ||| LV EF (biplane Simpson or 5/6 area-length method) LV eccentricity index57LV eccentricity index57 LV strain (global)53LV strain (global)53 3D LV volumes and function66 | |||| |Other|| Presence and severity of pericardial effusion (none, small, moderate, large)74 |

EF indicates ejection fraction; FAC, fractional area of change; LV, left ventricle; MPI, myocardial performance index; RA, right atrium; RV, right ventricle; TAPSE, tricuspid annular planar systolic excursion; 3D, 3-dimensional; TR, tricuspid regurgitation; and 2D, 2-dimensional.

Treatment

The rarity of death and transplantation in childhood has necessitated the reliance on surrogate markers such as acute change in pressure or resistance to understand responses to therapy. Inherent to this approach is the uncertainty of the

relationship between surrogate markers and the effect of a therapy. That is, surrogate markers may be associated with a disease but not be part of the pathophysiology of the disease, may not be sensitive to the intervention, or are part of a pathway that is not affected by the intervention. The limitations of surrogates compared with clinically meaningful outcomes, including quality of life and survival, must be understood in order to interpret therapy response.

Pharmacotherapy

Pharmacotherapy is commonly used in the management of PH–congenital heart disease, and hemodynamic studies demonstrating elevated PVR are usually performed before initiation. Therapy requires an exact morphological and functional diagnosis. The goals of therapy are to improve hemodynamics and quality of life. Therapy can be considered in context of specific treatment paradigms: (1) treat to close, meaning lowering the PVR to facilitate safe repair; (2) treat after repair of the defect(s); (3) improve quality of life in patients with ES; or (4) further lower pulmonary artery pressures and PVR in patients with pulmonary hypertensive vascular disease and Fontan circulations to improve forward pulmonary artery flow.

For targeted PH therapy, 3 classes of drugs are available: (1) phosphodiesterase-5 inhibitors, (2) endothelin receptor antagonists (ERAs), and (3) prostacyclins. Phosphodiesterase-5 inhibitors such as sildenafil and tadalafil are commonly used drugs shown to improve both hemodynamics and exercise capacity in patients with PAH–congenital heart disease, 91 including those with ES. 92 Hemodynamic benefits have also been shown in patients with univentricular circulation after cavopulmonary anastomosis. 93–95 ERAs are recommended in the setting of congenital heart disease because endothelin-1 has been shown to be a potent mediator of vascular constriction. 96 Single-center clinical trials of bosentan

Table 5. Advantages and Disadvantages of Cardiac Magnetic Imaging and Cardiac Tomography

||MRI|C| |---|---|---| |Advantages| High-resolution imaging of intracardiac and extracardiac vascular anatomy Reference standard for ventricular size, mass, stroke volume, and EF | High-resolution imaging of extracardiac vascular anatomy Short imaging time minimizing sedation needs | |||| || No exposure to ionizing radiation || ||| Delineation of pulmonary parenchyma Multiplanar reconstruction to view structures in 3 dimensions simultaneously Not limited by body habitus or scar tissue Detection of segmental and subsegmental pulmonary embolism Dual-energy CT scan quantifies lung perfusion | || Multiplanar reconstruction to view structures in 3 dimensions simultaneously Not limited by body habitus or scar tissue Phase-contrast imaging allows evaluation of flow (antegrade and retrograde) | Delineation of pulmonary parenchyma Multiplanar reconstruction to view structures in 3 dimensions simultaneously Not limited by body habitus or scar tissue Detection of segmental and subsegmental pulmonary embolism Dual-energy CT scan quantifies lung perfusion | |||| || across vascular structures Detection of myocardial fibrosis | Not limited by body habitus or scar tissue Detection of segmental and subsegmental pulmonary embolism Dual-energy CT scan quantifies lung perfusion Evaluation of pulmonary vasculature Evaluation of the pericardium Exposure to ionizing radiation Life-threatening reaction to iodinated contrast | || Evaluation of the pericardium| Not limited by body habitus or scar tissue Detection of segmental and subsegmental pulmonary embolism Dual-energy CT scan quantifies lung perfusion Evaluation of pulmonary vasculature Evaluation of the pericardium Exposure to ionizing radiation Life-threatening reaction to iodinated contrast | | Disadvantages|Long scan time| Not limited by body habitus or scar tissue Detection of segmental and subsegmental pulmonary embolism Dual-energy CT scan quantifies lung perfusion Evaluation of pulmonary vasculature Evaluation of the pericardium Exposure to ionizing radiation Life-threatening reaction to iodinated contrast | ||Need for breath holding| Not limited by body habitus or scar tissue Detection of segmental and subsegmental pulmonary embolism Dual-energy CT scan quantifies lung perfusion Evaluation of pulmonary vasculature Evaluation of the pericardium Exposure to ionizing radiation Life-threatening reaction to iodinated contrast | || Metallic prosthetic valves and implanted devices may cause| Not limited by body habitus or scar tissue Detection of segmental and subsegmental pulmonary embolism Dual-energy CT scan quantifies lung perfusion Evaluation of pulmonary vasculature Evaluation of the pericardium Exposure to ionizing radiation Life-threatening reaction to iodinated contrast | || susceptibility artifact, obscuring anatomy|| || Requires electrocardiographic gating|| ||Gadolinium-based contrast associated with rare nephrogenic systemic fibro-|| |||| ||Concentration-dependent retention of gadolinium in brains after|| || repeated gadolinium-based contrast||

CT indicates computed tomography; EF, ejection fraction; and MRI, magnetic resonance imaging.

and ambrisentan but not macitentan have been shown to be efficacious in improving hemodynamics in patients with congenital heart disease and ES. 97,98 Larger studies of ERAs are warranted. Patients on medical therapy warrant interval monitoring with echocardiograms and repeat hemodynamic evaluations, most often done 6 to 12 months after initiation of therapy and yearly once established on therapy, although no current recommendations are in place.

Nursing Considerations

Given the complexity of drug delivery, prescription management, and transition from inpatient to outpatient therapy, a specialized team approach is critical for therapeutic success. This is particularly true with multidrug therapies and parenteral prostacyclins. Advanced practice professionals, nurses, and specialty pharmacies provide a vital role in supporting patients with prostacyclin infusions. These teams provide targeted education and expertise in troubleshooting the challenges that patients often face, including high-risk situations such as management during a continuous prostacyclin infusion interruption with potential for “rebound” PH from line break or occlusion. 99,100

Surgical Repair of Patients With PAH–Congenital Heart Disease and Biventricular Circulations

For patients with PAH–congenital heart disease and shunts, early repair and elimination of the shunt are paramount to reduce the overall burden of pulmonary vascular disease. 101 Although there are no definitive data demonstrating specific outcomes at specified PVR thresholds, most pediatric guidelines suggest relatively safe closure up to a PVRi < 4 WU∙m 2 and a PVR/systemic vascular resistance ratio ${<\!0.3}$ to 0.5 with evidence of reactivity with acute vasoreactivity testing. 2 In patients who have a PVRi between 4 and 8 WU∙m 2 with limited or no reactivity, management of their pulmonary vascular disease with pharmacotherapy and subsequent surveillance catheterizations demonstrating significant decrease in PVRi may aid in surgical decision-making for possible partial or complete shunt closure. 18,102,103 Consideration of fenestrated closures of defects to reduce Qp but still allow a decompressive shunt if needed may also be considered in highrisk populations. In adults in whom therapy is being used in a treat-to-repair context, evidence is incomplete. In recent European Respiratory Society/European Society of Cardiology guidelines, patients with an atrial septal defect, a PVR > 5 WU∙m 2 , and a fall in PVR to < 5 WU∙m 2 after therapy may undergo surgery, but an individualized approach is required for patients with other defects. 104 The long-term outcome of such a strategy requires further investigation.

Surgical Repair/Palliation of PAH–Congenital Heart Disease and Univentricular Circulations

For patients with univentricular circulations and a requirement for passive pulmonary blood flow, current recommendations are for next-stage palliation if the

PVRi is < 3 WU∙m 2 and the transpulmonary gradient is ${\sf<}6\ {\sf m m}\,{\sf H g}$ and use of a fenestration in the Fontan circuit to act as pop-off, especially in the early postoperative period. 16 In a recent meta-analysis, both ERAs and phosphodiesterase-5 inhibitors have been shown to lower the PVR of patients with Fontan physiology, to reduce New York Heart Association functional class, to increase 6-minute walk distance, and to improve peak oxygen consumption; however, no significant change was observed in mortality. 93,104 Although both ERAs and phosphodiesterase-5 inhibitors are often used in this particular cohort to lower PVR, a paucity of data demonstrating true efficacy remains.

Palliation of PAH–Congenital Heart Disease Through Pulmonary-to-Systemic (Reversed Potts Shunt) Shunt Creation

Creation of a pulmonary-to-systemic shunt (reversed Potts shunt) through either a surgical or an interventional catheterization approach has been increasingly used in patients with suprasystemic pulmonary artery pressures and progressive RV dysfunction despite pharmacotherapy. 105–108 Such a strategy is of value in patients with PAH after surgical correction of congenital heart disease in the setting of failure of maximal medical therapy. Recent results from an international registry published by Grady et al 108 have demonstrated successful palliation of patients with this approach, with improvement in exercise parameters and World Health Organization functional status and a decrease in pharmacotherapy burden, which may facilitate weaning of parenteral prostanoids. Whether lung transplantation is advisable after a Potts shunt and whether a Potts shunt should precede continuous prostacyclin therapy remain controversial. The presence of a Potts shunt may complicate a subsequent lung transplantation.

Lung Transplantation

In patients with severe PAH–congenital heart disease after repair or in those with insignificant shunts, the clinical course is similar to that for IPAH, and transplantation evaluation is appropriate along with maximal medical therapy. Expected survival for a patient with ES compared with survival after lung transplantation should be seriously considered before the patient is listed for transplantation. In patients with PAH with progressive right-sided heart failure and associated end-organ injury, posttransplantation mortality is significantly higher and often requires extracorporeal membrane oxygenation support as a bridge to recovery or lung transplantation. Therefore, eligible patients in World Health Organization functional class IIIb and IV should have timely discussions of end-stage goals and be referred for transplantation evaluation.

Double-lung transplantation is the most common consideration for patients with congenital heart disease and end-stage PH and offers shorter wait-list times and improved organ use compared with heart-lung

transplantation. Patients with ES associated with atrial or ventricular septal defect or patent ductus arteriosus can undergo double-lung transplantation combined with repair of these cardiac defects. 109

Heart-Lung Transplantation

Although overall technically easier than double-lung transplantation, heart-lung transplantation prevalence among patients with congenital heart disease has declined significantly worldwide over the past decade because of the success of double-lung transplantation in conjunction with aggressive treatment of early RV dysfunction. 110,111 Conditions for which heart-lung transplantation is the best option include ES in conjunction with severely compromised RV or left ventricular function or complex PH–congenital heart disease and associated pulmonary vein stenosis.

Transplantation Outcomes

Overall, early survival (eg, perioperative or 3 month) outcomes for patients with PAH are the lowest among all lung transplant recipients, with higher posttransplantation mortality after bridging with extracorporeal membrane oxygenation. However, 5- and 10-year survival rates are similar to rates for those with transplantation for other pathogeneses. 112 However, 1-year survival for transplant recipients for PAH is significantly better than survival for transplant recipients with primary lung disease.

SOCIAL DETERMINANTS OF HEALTH IN PH–CONGENITAL HEART DISEASE

An analysis of the PPHNet registry (Pediatric Pulmonary Hypertension Network) found significant racial variability in the prevalence of PH subtypes and survival in children with PH. 113 Karamlou et al 114 elucidated the interaction between Black race and neonatal age: Black neonates admitted for congenital heart disease care had better survival but longer length of hospital stay than neonates from other ethnicities and races, suggesting that modification of inpatient processes may mitigate risk. 114–116 Current literature highlights the following inequalities: (1) People of color and lower socioeconomic status are associated with a higher incidence of cardiovascular death; (2) $42\%$ of the US population in 2020 belonged to underrepresented races and ethnicities; and (3) survival in PAH is dependent on both early diagnosis and early institution of therapy. 117–119 Despite these potential precipitants, research to further elucidate the relationship between health disparities and PAH is challenged because clinical registries and trials have not traditionally had adequate representation of racial and ethnic and socioeconomically fragile populations. In addition, socioeconomic and geographic barriers and social determinants of health can disproportionally affect

underrepresented racial and ethnic groups’ access to and safe provision of medically indicated advanced care, including heart transplantation and heart-lung transplantation. When possible, these factors must be addressed to promote equitable delivery of care. Availability of subspecialty care will continue to affect patients in parts of the world where advanced medical, surgical, and transplantation therapies are unavailable. 117,120

PROGNOSIS

The prognosis for patients with PH can vary significantly, both between those with PH with different WSPH classifications and between those within the same classification category. Nevertheless, for any subgroup, prognosis is also greatly influenced by socioeconomic factors, general medical care, access to PH treatment, availability of medications, use of combination therapy, and partial or total repair after the PH diagnosis. Addressing those patients with PH–congenital heart disease specifically, van Loon and colleagues 19 nicely demonstrated that patients with PH–congenital heart disease tend to have better outcomes than patients with idiopathic PH (1-, 3-, and 5-year survival rates of $73\%$ , $63\%$ , and $60\%$ versus $62\%$ , $50\%$ , and $46\%$ ). Of particular interest within the van Loon et al data was the demonstration that a subgroup of infants with posttricuspid shunts had worse survival than those with IPAH. Children with concurrent genetic syndromes and congenital heart disease also were at risk for accelerated development of pulmonary vascular disease and worse outcomes. Current registry studies are ongoing to look at prognosis for pediatric patients with PH. Patients with ES are known to have better survival than those with unrepaired congenital heart disease who do not develop traditional Eisenmenger physiology or those who undergo shunt closure but have continued evidence of pulmonary vascular disease. 18,19,102,121,122 Prognostic factors for worse outcomes in patients with ES include complex heart defects, 123 increasing age, pretricuspid shunt, oxygen saturation at rest, presence of sinus rhythm, elevated NT-proBNP, and presence of pericardial effusion.

Patients with coincidental shunt have shown outcomes similar to those of patients with IPAH, whereas patients with unrestricted, predominant left-to-right shunt, and high PVR have the best prognosis. 124 In this last group of patients, because there are not enough data on the long-term impact of defect closure, the better prognosis in this subgroup should be kept in mind when considering the operability of these patients, in whom outcome may worsen if PH persists or recurs after defect closure. The patient’s age and comorbidities, exercise-induced desaturation, and response during vasoreactivity testing; the center experience; the availability of PH therapy after surgery; and the

genetic background all influence outcomes. Although some published cases and short series have raised the option of the so-called treat-and-repair strategy, 18,102,103 large series with long-term follow-up are still needed to provide criteria to select the patients who benefit most from this strategy.

FUTURE DIRECTIONS AND RESEARCH

Multiple opportunities exist to improve the care of patients with PH–congenital heart disease. From imaging to tailored pharmacotherapy strategies based on anatomical lesion, the possibilities are limitless. For example, patients would benefit from the development of an echocardiography score that could reduce the number of cardiac catheterizations needed in a lifetime to guide disease management. Improvements in cross-sectional cardiac imaging to refine the evaluation of flow in the pulmonary bed and to assess PVR could serve a similar role. In addition, targeted application of artificial intelligence in cardiac imaging could drive the synthesizing of multimodality data into meaningful analytics to inform patient management.

With early diagnosis and management of simple congenital heart disease and prolonged survival of individuals with complex congenital heart disease, the paradigm of PH–congenital heart disease has shifted toward more complex adult patients whose survival is similar to that of patients with IPAH and worse than that of patients with ES. New insights from randomized controlled trials using medications for ES have shown variable but primarily positive results with improvement in 6-minute walk distance and PVRi. 97,125–127 However,

these trials have yet to include patients with complex congenital heart disease and those with PH after shunt closure. In patients with PH after shunt closure or those with smaller incident shunts, the use of a reversed Potts shunt seems a promising alternative to improve quality of life and survival. 108,128 Last, ambulatory extracorporeal membrane oxygenation as a bridge to recovery in pregnant patients with ES before delivery and other adult patients with PH–congenital heart disease as a bridge to recovery or lung transplantation may improve overall survival. 129,130

CONCLUSIONS

PH–congenital heart disease in its various forms carries strikingly different management strategies, is increasingly recognized as a particularly challenging type of PH to manage, and requires nuanced, expert management to improve survival. However, much remains unknown about these patients, from the inciting pathophysiology to their optimal management. Ultimately, understanding the cause and pathophysiology of PH in congenital heart disease within the various subgroups will allow targeted drug development and effective treatment strategies. Although great strides have been made in the management of patients with PH in general, as well as those with PH–congenital heart disease, significant gaps remain that demand targeted research endeavors. Sustained and committed multidisciplinary collaboration remains key to reducing the global medical burden caused by pulmonary vascular disease associated with congenital heart disease, the most preventable cause of PH.

Disclosures

Writing Group Disclosures

| Writing group member |Employment|Research grant| Other research support | Speakers' bureau/ honoraria | Expert witness | Ownership interest | Consultant/ advisory board |Other| |---|---|---|---|---|---|---|---|---| |Pei-Ni Jone| Lurie Children's Hospital |None|None|None|None|None|None|None| | Usha S. Krishnan | Columbia University Medical Center/New York Presbyterian Hospital | Janssen-Actelion (CUIMC receives funding; she has no financial benefit. Pl for sponsored research)*; United Therapeutics (CUIMC receives fund- ing; she has no finan- |None|None|None|None|None|None| |||||||||| | Ryan D. Coleman | Texas Children's Hos- pital, Baylor College of Medicine |None|None|None|None|None|None|None| | Maria Jesus del Cerro Marin | Hospital Universita- rio Ramon y Cajal (Spain) |None|None|Janssen*|None|None|Ferrer*|None|

Writing Group Disclosures Continued

| Writing group member |Employment|Research grant | Other research support | Speakers' bureau/ honoraria | Expert witness | Ownership interest | Consultant/ advisory board |Other| |---|---|---|---|---|---|---|---|---| | Pirooz Eghtesady | Washington Uni- versity School of Medicine |None|None|None|None|None|None|None| | Amanda Hauck | Ann Robert Lurie Children's Hospital of Chicago, Northwestern University |None|None|None|None|None|None|None| | D.Dunbar Ivy | University of Colo- rado Health Sciences Center | Janssent; Bayer*; FDAt (all funds go to institution) |None|None|None|None| Janssen (un- paid)*; Merck- Acceleron (unpaid)*; Gos- samer Bio (unpaid)*; GSK (unpaid)*; Alta- vant (unpaid)*; Association of Pediatric Pulmonary Hy- pertension* |None| | Tara Karam- Iou | Cleveland Clinic Foundation |None|None|None|None|None| Edwards Life- sciences* |None| | JuanPablo Sandoval | Ignacio Chavez National Institute of Cardiology (Mexico) |None|None|None|None|None|None|None| | Kathryn Till- man | Medical College of Wisconsin- Children's Wisconsin |None|None|None|None|None|None|None| |Uyen Truong| Children's National Hospital Washington D.C. |None|None|None|None|None|None|None|

This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $\S5000$ or more during any 12-month period, or $5\%$ or more of the person’s gross income; or (b) the person owns $5\%$ or more of the voting stock or share of the entity, or owns $\S5000$ or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition. \*Modest.

†Significant.

Reviewer Disclosures

|Reviewer|Employment| Research grant | Other research support | Speakers' bureau/ honoraria | Expert witness | Ownership interest | Consultant/ advisory board |Other| |---|---|---|---|---|---|---|---|---| | Catherine Avitabile | Children's Hospital of Philadelphia/ University of Pennsylvania |None|None|None|None|None|None|None| | Martin Koesten- berger | Division of Pediatric Cardiology, Department of Pediatrics, Grown- Up Congenital Heart Disease Unit, Medical University Graz (Austria) |None|None|None|None|None|None|None| | Shahin Moledina | Great Ormond Street Hospital for Children NHS Foundation Trust (United Kingdom) |None|None|None|None|None|None|None| |Rohit Rao|UCSD|None|None|None|None|None|None|None| | Dietmar Schranz | Pediatric Heart Center, Johann-Wolfgang-Goethe University Clinic (Germany) |None|None|None|None|None|None|None|

This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $\S5000$ or more during any 12-month period, or $5\%$ or more of the person’s gross income; or (b) the person owns $5\%$ or more of the voting stock or share of the entity, or owns $\S5000$ or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.

ARTICLE INFORMATION

The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.

This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on March 14, 2023, and the American Heart Association Executive Committee on April 4, 2023. A copy of the document is available at https://professional.heart.org/statements by using either “Search for Guidelines & Statements” or the “Browse by Topic” area. To purchase additional reprints, call 215-356-2721 or email Meredith.Edelman@wolterskluwer.com.

The American Heart Association requests that this document be cited as follows: Jone P-N, Ivy DD, Hauck A, Karamlou T, Truong U, Coleman RD, Sandoval JP, del Cerro Marín MJ, Eghtesady P, Tillman K, Krishnan US; on behalf of the American Heart Association Congenital Cardiac Defect Committee of the Council on Lifelong Congenital Heart Disease and Heart Health in the Young; Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Surgery and Anesthesia; Council on Clinical Cardiology; and Council on Peripheral Vascular Disease. Pulmonary hypertension in congenital heart disease: a scientific statement from the American Heart Association. Circ Heart Fail . 2023;16:e00080. doi: 10.1161/HHF.0000000000000080

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