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Jone Et Al 2023 Pulmonary Hypertension in Congenital Heart Disease A Scientific Statement From The American Heart
Jone Et Al 2023 Pulmonary Hypertension in Congenital Heart Disease A Scientific Statement From The American Heart
ABSTRACT: Patients with pulmonary hypertension associated with congenital heart disease make up an increasing proportion
of the total pulmonary hypertension population who bring with them added complexity because of underlying anatomical
and hemodynamic abnormalities. Currently, no consensus recommendations are available on how to best manage this group
of patients for either the primary cardiologist or pulmonary hypertension subspecialist, including timing of referral. The
purposes of this document are (1) to describe the various pulmonary hypertension groups and subgroups associated with
congenital heart disease, (2) to describe imaging modalities used in patient evaluation, (3) to elucidate medical and surgical
management considerations, (4) to highlight disparities within this population, and (5) to identify gaps and future research
needs of patients with pulmonary hypertension associated with congenital heart disease.
Key Words: AHA Scientific Statements ◼ congenital heart disease ◼ pediatric pulmonary hypertension ◼ prognosis
◼ pulmonary arterial hypertension ◼ treatment
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P
ulmonary hypertension (PH) is now defined as mean heart disease have led to increased survival into adult-
pulmonary artery pressure >20 mm Hg according to hood. This improved survival is accompanied by a signifi-
the updated clinical classification from the 6th World cant number of associated cardiac sequelae, including
Symposium of Pulmonary Hypertension (WSPH) and arrhythmias, postoperative valvar and vascular structural
has many causes (Table 1).1 PH can be associated with defects, ventricular dysfunction, and PH.
various forms of congenital heart disease and can pres- Although expert guidelines are available for PH,
ent at different ages, depending on the lesion. Pulmo- there is a relative lack of definitive levels of evidence
nary arterial hypertension (PAH) is a specific subgroup for the management of PH associated with congeni-
of PH characterized hemodynamically by the presence of tal heart disease. These patients are typically under-
precapillary PH, including an end-expiratory pulmonary represented in or excluded from clinical studies and
artery wedge pressure ≤15 mm Hg and pulmonary vas- therefore have been the focus of only a small number
cular resistance (PVR) ≥3 Wood units (WU).1 In children, of dedicated clinical trials. The limited prospective trial
PVR is indexed as recommended by the pediatric con- data means that treatment strategies are often based
sensus task force.2 In children with complex congenital on the experience of clinical experts or on findings
heart disease, including univentricular heart, and those from small single-center or unmatched retrospective
with segmental PH or mixed group 1 and 2 PH, diag- data and should be tailored to the individual patient’s
nosis and management of PH have to be tailored to the structural and hemodynamic issues. Management of
individual patient’s unique anatomical and hemodynamic this cohort can be lesion-specific and can determine
condition. The incidence and prevalence of PAH associ- whether the underlying congenital heart disease can
ated with congenital heart disease were reported to be be safely repaired. The purposes of this document
2.2 and 15.6 per 1 million, respectively.3,4 The improve- are to review the various PH groups and subgroups
ments in diagnosis and management of congenital associated with congenital heart disease within the
pulmonary to predominantly pulmonary to systemic. likely not repairable with physiology closer to
The hallmark of ES is cyanosis with consequences Eisenmenger physiology (when PVR >8 WU∙m2).2
of chronic hypoxemia, including secondary erythro- A third group has an intermediate status (PVR,
cytosis and multisystem involvement.14 4–8 WU∙m2) and should be considered for tar-
2. Unrepaired moderate to large defects with mildly geted PH therapy with re-evaluation for operability
to moderately elevated PVR with predominantly on an individual basis.2 Individual clinical charac-
left-to-right shunt form the second subgroup of teristics, including age, shunt location, associated
PAH–congenital heart disease. This group has diagnoses, and saturations, must be considered
considerable heterogeneity in outcome, depending when determining appropriateness for intervention.
on the severity and reversibility of vascular remod- 3. PAH with coincidental congenital heart disease
eling.6 Criteria for operability incorporating baseline includes the subset of patients with small pretri-
hemodynamics and response to acute vasodilator cuspid or posttricuspid shunts associated with
testing have been proposed (Table 2).15,16 Patients PAH. These defects are considered coincidental
can be divided into those in whom congenital heart and not causative of the degree of PAH. These
disease is still possibly repairable (PVR <4 WU∙m2) patients have a clinical course and poor survival,
and those in whom congenital heart disease is similar to patients with IPAH.2,17,18
4. Persistent or recurrent PAH after surgical repair of this category. Although there are data on the use
congenital heart disease is associated with poor of vasoreactivity testing to determine operability,
prognosis.2,17,18 To date, there are no sufficiently these studies have not been proven sufficiently
reliable data to predict which patients will fall into reliable.17,18
In group 2 PH, left-sided heart disease is increasingly 3. Scimitar syndrome is a distinct form of partial
recognized as a cause of PH in congenital heart disease anomalous pulmonary venous drainage of right pul-
and may progressively develop over time.19 It occurs monary veins to the inferior vena cava with associ-
in the setting of elevated pulmonary venous pressure, ated right lung hypoplasia and anomalous systemic
resulting in a proportional elevation of precapillary pul- arterial supply to a portion of the right lung. PH can
monary artery pressure (isolated postcapillary PH) or PH develop as a result of variable mechanisms, includ-
in excess of the pulmonary venous hypertension with ing associated congenital heart disease, excessive
associated pulmonary vascular disease (PVR ≥3 WU∙m2), pulmonary blood flow, systemic arterial supply of
referred to as combined precapillary and postcapillary pulmonary segments, obstructed pulmonary veins,
PH.1 Congenital cardiac lesions that belong to WSPH or their combination.24 Presentation in infancy with
group 2.4 include those that directly obstruct pulmonary pulmonary hypertensive vascular disease portends
venous or left atrial flow and those that indirectly result a worse prognosis.25
in left atrial hypertension due to elevated left ventricular
filling pressures (Table 2).2 It is important to recognize that many pediatric patients
Group 4.2.5 PH has been classified in the 6th WSPH may have multiple reasons for PH and simultaneously
classification as a subgroup of PH due to pulmonary have features of different PH groups, as seen in patients
artery obstructions. However, this rare subgroup of pedi- with Down syndrome with PAH–congenital heart dis-
atric patients has not been evaluated for the presence ease. Down syndrome is associated with lung hypoplasia
of distal pulmonary vascular disease (as may be seen in and alveolar simplification, which is complicated by other
chronic thromboembolic PH), and their response to tar- comorbidities such as congenital heart disease, persis-
geted therapy has not been studied (Table 2). tent PH of the newborn, thyroid disease, sleep-disordered
Group 5.4 PH includes PH with unclear or multifacto- breathing, and prematurity, and other vascular disorders
rial mechanisms such as single-ventricle physiology, seg- such as Moyamoya disease are common cotravelers.26,27
mental PH, and scimitar syndrome (Table 2).2 Biomarkers such as NT-proBNP (N-terminal pro-B-type
natriuretic peptide) and galectin-3 may help distinguish
1. Functional single-ventricle circulation encom- between children with Down syndrome with and those
passes anatomical defects with an effective sin- without PH.28 Genetic abnormalities in children may pre-
gle ventricular pump driving both systemic and dispose to antiangiogenesis (COL18a1 [endostatin]), a
pulmonary circulations. Staged palliation, culmi- proinflammatory state (IFNAR1/2 [interferon α/β recep-
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nating in the Fontan repair, directs caval return tors 1 and 2]), and lung disease, all contributing to PH.27
directly to the pulmonary arteries, resulting in pas- Future genetic studies will further our understanding of
sive, nonpulsatile pulmonary blood flow requiring the role of underlying molecular pathways compared
an unobstructed pathway with low PVR. Patients with physiologically induced mechanisms and their
with nonpulsatile cavopulmonary flow can develop potential overlap, which could in turn determine poten-
microvascular remodeling that results in a failed tial responses to therapies and thus lead to even further
Fontan state, which affects survival.20 The PH diag- modifications of classifications.
nostic definition of mean pulmonary artery pressure
≥20 mm Hg is irrelevant in the Fontan circulation;
instead, pulmonary hypertensive vascular disease SCREENING AND DIAGNOSING PH–
for univentricular circulations is defined as a mean CONGENITAL HEART DISEASE
transpulmonary gradient >6 mm Hg and an PVRi
>3 WU∙m2.21,22 Measurement of PVR is challenging Clinical Presentation and Initial Testing
in this group because of additional sources of pul- Symptoms of PH in children are frequently subtle and may
monary blood flow, residual antegrade pulmonary delay the diagnosis of PAH–congenital heart disease. In
flow, segmental pulmonary arterial stenoses, and infants, poor feeding, tachypnea, tachycardia, and poor
flow across the Fontan fenestrations. growth are common. Syncope is rare in ES, but shortness
2. Segmental PH occurs when different lung seg- of breath is common.29 Physical signs may include a loud
ments develop varying degrees of pulmonary split second heart sound, gallop, and holosystolic mur-
hypertensive vascular disease, with at least 1 seg- mur of tricuspid regurgitation. Edema of the face, hands,
ment of pulmonary vasculature remaining non- ankles, and hepatomegaly is a later sign of right-sided
hypertensive.23 There is often an aortic source of heart failure.30 Chest radiographs may provide clues to
pulmonary blood flow to a portion of the lungs, as the degree of shunting in children with associated PAH–
well as the presence of segmental branch pulmo- congenital heart disease. Congested vasculature is often
nary artery stenosis or the presence of segmental seen in large left-to-right intracardiac shunts. Oligemia
branch pulmonary artery stenosis, either alone or in may be present in patients with restricted blood flow
combination with other congenital heart defects. such as those with ES. However, radiographic findings
do not always correlate with disease severity. Evidence advantages and disadvantages (Table 5). Patients with
of right ventricular (RV) hypertrophy on ECG is present metallic prosthetic valves and implanted devices, includ-
in most children with PH. Some studies have suggested ing pacemakers, may not be able to undergo magnetic
that the specificity (69%) and positive predictive value resonance imaging scanning because of either the pres-
(67%) of ECG are low in children with a diagnosis of PH ence of abandoned leads or metallic artifact obscuring
by echocardiography.31 In a study of 456 children in the vital structures of interest. Gadolinium-based magnetic
TOPP registry (Tracking Outcomes and Practice in Pae- resonance contrast has the rare risk of nephrogenic sys-
diatric Pulmonary Hypertension) with catheterization- temic fibrosis seen with impaired renal function. Data
proven PH, no child with PH had a normal chest x-ray, have emerged on concentration-dependent retention of
ECG, and echocardiogram.32 gadolinium in brains of patients who received repeated
gadolinium-based contrast.77,78 Clinical effects in children
Transthoracic Echocardiography
are not yet known.
Transthoracic echocardiography is the first-line cardio-
vascular imaging modality for the diagnosis of PH. It is
Cardiac Catheterization
the most accessible noninvasive tool used for routine
Right- and left-sided heart catheterization is consid-
assessment33–40 and for serial follow-up of PH associ-
ered the gold standard for measuring hemodynamics
ated with congenital heart disease.41,42 Developments
in patients with congenital heart disease and advanced
in echocardiography have led to new insights into the
pulmonary vascular disease, especially to assess oper-
structure and function of the RV and its role in PH.43,44
ability.22,79,80 Acute vasoreactivity testing is performed at
Conventional echocardiography-based imaging includes
the time of catheterization and helps strategize treat-
assessment of anatomy in 2 dimensions, hemodynamics
ment for postoperative PH. When available, inhaled
through Doppler echocardiography, and qualitative and
nitric oxide (20–80 ppm) alone or in combination with
quantitative evaluation of RV and left ventricular func-
oxygen is considered the preferred agent for vasodila-
tion.35–37,41,45–47 Advanced echocardiography includes
tor testing.79,81–83 It is safe and short acting and offers
evaluation of right-sided heart size and function, myocar-
a better pulmonary vasodilator effect than systemic
dial mechanics, and estimated ratio of RV to pulmonary
agents. However, nitric oxide is not always affordable
arterial coupling.48–56 Table 3 shows the advantages and
and thus is not readily available in all cardiac cath-
limitations of each of echocardiographic techniques used
eterization laboratories, particularly in low- to middle-
in pediatric PH. Different echocardiography parameters
income countries. Alternative vasodilator agents include
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Table 4. Echocardiographic Views to Obtain Hemodynamic relationship between surrogate markers and the effect of a
and Functional Parameters in Patients With PH therapy. That is, surrogate markers may be associated with
Echo view Functional parameters a disease but not be part of the pathophysiology of the dis-
Doppler Parasternal short Pulmonary acceleration time/ejection time ease, may not be sensitive to the intervention, or are part
axis Pulmonary regurgitation early and late of a pathway that is not affected by the intervention. The
diastolic velocity
limitations of surrogates compared with clinically meaning-
Apical 4 chamber TR severity (none, mild, moderate, severe) ful outcomes, including quality of life and survival, must be
TR peak velocity
MPI (tricuspid tissue Doppler)71 understood in order to interpret therapy response.
Systolic/diastolic duration ratio from TR
Doppler61 Pharmacotherapy
Tissue Doppler systolic and diastolic Pharmacotherapy is commonly used in the management
velocities (tricuspid, septal, mitral)
of PH–congenital heart disease, and hemodynamic stud-
RA Apical 4 chamber RA area, RA strain61
ies demonstrating elevated PVR are usually performed
RV Apical 4 chamber Qualitative RV function (good, mildly/ before initiation. Therapy requires an exact morphologi-
moderately/severely depressed)
RV end diastolic and end-systolic cal and functional diagnosis. The goals of therapy are to
dimensions indexed for BSA (2D) improve hemodynamics and quality of life. Therapy can
FAC percent be considered in context of specific treatment paradigms:
TAPSE with z score (M mode when
available, 2D) (1) treat to close, meaning lowering the PVR to facili-
RV strain (global and segmental)51,72,73 tate safe repair; (2) treat after repair of the defect(s); (3)
3D RV volumes and function50,51 improve quality of life in patients with ES; or (4) further
LV Apical 2+4 LV EF (biplane Simpson or 5/6 area-length lower pulmonary artery pressures and PVR in patients
chamber method)
LV eccentricity index57
with pulmonary hypertensive vascular disease and Fon-
LV strain (global)53 tan circulations to improve forward pulmonary artery flow.
3D LV volumes and function66 For targeted PH therapy, 3 classes of drugs are avail-
Other Presence and severity of pericardial effusion able: (1) phosphodiesterase-5 inhibitors, (2) endothe-
(none, small, moderate, large)74 lin receptor antagonists (ERAs), and (3) prostacyclins.
EF indicates ejection fraction; FAC, fractional area of change; LV, left ventricle; Phosphodiesterase-5 inhibitors such as sildenafil and
MPI, myocardial performance index; RA, right atrium; RV, right ventricle; TAPSE,
tricuspid annular planar systolic excursion; 3D, 3-dimensional; TR, tricuspid regur-
tadalafil are commonly used drugs shown to improve
gitation; and 2D, 2-dimensional. both hemodynamics and exercise capacity in patients
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Table 5. Advantages and Disadvantages of Cardiac Magnetic Imaging and Cardiac Tomography
MRI CT
Advantages High-resolution imaging of intracardiac and extracardiac vascular anatomy High-resolution imaging of extracardiac vascular anatomy
Reference standard for ventricular size, mass, stroke volume, and EF Short imaging time minimizing sedation needs
High reproducibility for serial monitoring Delineation of pulmonary parenchyma
No exposure to ionizing radiation Multiplanar reconstruction to view structures in 3 dimensions
Multiplanar reconstruction to view structures in 3 dimensions simultaneously simultaneously
Not limited by body habitus or scar tissue Not limited by body habitus or scar tissue
Phase-contrast imaging allows evaluation of flow (antegrade and retrograde) Detection of segmental and subsegmental pulmonary embolism
across vascular structures Dual-energy CT scan quantifies lung perfusion
Detection of myocardial fibrosis Evaluation of pulmonary vasculature
Evaluation of the pericardium Evaluation of the pericardium
Disadvantages Long scan time Exposure to ionizing radiation
Need for breath holding Life-threatening reaction to iodinated contrast
Metallic prosthetic valves and implanted devices may cause
susceptibility artifact, obscuring anatomy
Requires electrocardiographic gating
Gadolinium-based contrast associated with rare nephrogenic systemic fibro-
sis seen with impaired renal function
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 PVRi is <3 WU∙m2 and the transpulmonary gradient
to be efficacious in improving hemodynamics in patients is <6 mm Hg and use of a fenestration in the Fontan
with congenital heart disease and ES.97,98 Larger stud- circuit to act as pop-off, especially in the early postop-
ies of ERAs are warranted. Patients on medical therapy erative period.16 In a recent meta-analysis, both ERAs
warrant interval monitoring with echocardiograms and and phosphodiesterase-5 inhibitors have been shown
repeat hemodynamic evaluations, most often done 6 to lower the PVR of patients with Fontan physiology, to
to 12 months after initiation of therapy and yearly once reduce New York Heart Association functional class, to
established on therapy, although no current recommen- increase 6-minute walk distance, and to improve peak
dations are in place. oxygen consumption; however, no significant change
was observed in mortality.93,104 Although both ERAs and
Nursing Considerations phosphodiesterase-5 inhibitors are often used in this
Given the complexity of drug delivery, prescription man- particular cohort to lower PVR, a paucity of data demon-
agement, and transition from inpatient to outpatient ther- strating true efficacy remains.
apy, a specialized team approach is critical for therapeutic
success. This is particularly true with multidrug therapies Palliation of PAH–Congenital Heart Disease
and parenteral prostacyclins. Advanced practice profes- Through Pulmonary-to-Systemic (Reversed Potts
sionals, nurses, and specialty pharmacies provide a vital Shunt) Shunt Creation
role in supporting patients with prostacyclin infusions. Creation of a pulmonary-to-systemic shunt (reversed
These teams provide targeted education and expertise in Potts shunt) through either a surgical or an interventional
troubleshooting the challenges that patients often face, catheterization approach has been increasingly used in
including high-risk situations such as management during patients with suprasystemic pulmonary artery pressures
a continuous prostacyclin infusion interruption with poten- and progressive RV dysfunction despite pharmacother-
tial for “rebound” PH from line break or occlusion.99,100 apy.105–108 Such a strategy is of value in patients with PAH
after surgical correction of congenital heart disease in
Surgical Repair of Patients With PAH–Congenital the setting of failure of maximal medical therapy. Recent
Heart Disease and Biventricular Circulations results from an international registry published by Grady et
For patients with PAH–congenital heart disease and al108 have demonstrated successful palliation of patients
shunts, early repair and elimination of the shunt are para- with this approach, with improvement in exercise parame-
mount to reduce the overall burden of pulmonary vascular ters and World Health Organization functional status and a
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disease.101 Although there are no definitive data demon- decrease in pharmacotherapy burden, which may facilitate
strating specific outcomes at specified PVR thresholds, weaning of parenteral prostanoids. Whether lung trans-
most pediatric guidelines suggest relatively safe closure plantation is advisable after a Potts shunt and whether a
up to a PVRi <4 WU∙m2 and a PVR/systemic vascular Potts shunt should precede continuous prostacyclin ther-
resistance ratio <0.3 to 0.5 with evidence of reactivity apy remain controversial. The presence of a Potts shunt
with acute vasoreactivity testing.2 In patients who have a may complicate a subsequent lung transplantation.
PVRi between 4 and 8 WU∙m2 with limited or no reactiv-
Lung Transplantation
ity, management of their pulmonary vascular disease with
In patients with severe PAH–congenital heart disease
pharmacotherapy and subsequent surveillance catheter-
after repair or in those with insignificant shunts, the clini-
izations demonstrating significant decrease in PVRi may
cal course is similar to that for IPAH, and transplantation
aid in surgical decision-making for possible partial or com-
evaluation is appropriate along with maximal medical
plete shunt closure.18,102,103 Consideration of fenestrated
therapy. Expected survival for a patient with ES com-
closures of defects to reduce Qp but still allow a decom-
pared with survival after lung transplantation should
pressive shunt if needed may also be considered in high-
be seriously considered before the patient is listed for
risk populations. In adults in whom therapy is being used in
transplantation. In patients with PAH with progressive
a treat-to-repair context, evidence is incomplete. In recent
right-sided heart failure and associated end-organ injury,
European Respiratory Society/European Society of Car-
posttransplantation mortality is significantly higher and
diology guidelines, patients with an atrial septal defect, a
often requires extracorporeal membrane oxygenation
PVR >5 WU∙m2, and a fall in PVR to <5 WU∙m2 after ther-
support as a bridge to recovery or lung transplantation.
apy may undergo surgery, but an individualized approach is
Therefore, eligible patients in World Health Organization
required for patients with other defects.104 The long-term
functional class IIIb and IV should have timely discus-
outcome of such a strategy requires further investigation.
sions of end-stage goals and be referred for transplan-
Surgical Repair/Palliation of PAH–Congenital Heart tation evaluation.
Disease and Univentricular Circulations Double-lung transplantation is the most common
For patients with univentricular circulations and a consideration for patients with congenital heart disease
requirement for passive pulmonary blood flow, current and end-stage PH and offers shorter wait-list times
recommendations are for next-stage palliation if the and improved organ use compared with heart-lung
transplantation. Patients with ES associated with atrial underrepresented racial and ethnic groups’ access to
or ventricular septal defect or patent ductus arteriosus and safe provision of medically indicated advanced care,
can undergo double-lung transplantation combined with including heart transplantation and heart-lung transplan-
repair of these cardiac defects.109 tation. When possible, these factors must be addressed
to promote equitable delivery of care. Availability of sub-
Heart-Lung Transplantation specialty care will continue to affect patients in parts of
Although overall technically easier than double-lung the world where advanced medical, surgical, and trans-
transplantation, heart-lung transplantation prevalence plantation therapies are unavailable.117,120
among patients with congenital heart disease has
declined significantly worldwide over the past decade
because of the success of double-lung transplantation in PROGNOSIS
conjunction with aggressive treatment of early RV dys- The prognosis for patients with PH can vary significantly,
function.110,111 Conditions for which heart-lung transplan- both between those with PH with different WSPH
tation is the best option include ES in conjunction with classifications and between those within the same
severely compromised RV or left ventricular function or classification category. Nevertheless, for any subgroup,
complex PH–congenital heart disease and associated prognosis is also greatly influenced by socioeconomic
pulmonary vein stenosis. factors, general medical care, access to PH treatment,
availability of medications, use of combination ther-
Transplantation Outcomes
apy, and partial or total repair after the PH diagnosis.
Overall, early survival (eg, perioperative or 3 month)
Addressing those patients with PH–congenital heart
outcomes for patients with PAH are the lowest among
disease specifically, van Loon and colleagues19 nicely
all lung transplant recipients, with higher posttrans-
demonstrated that patients with PH–congenital heart
plantation mortality after bridging with extracorporeal
disease tend to have better outcomes than patients
membrane oxygenation. However, 5- and 10-year
with idiopathic PH (1-, 3-, and 5-year survival rates
survival rates are similar to rates for those with trans-
of 73%, 63%, and 60% versus 62%, 50%, and 46%).
plantation for other pathogeneses.112 However, 1-year
Of particular interest within the van Loon et al data
survival for transplant recipients for PAH is significantly
was the demonstration that a subgroup of infants with
better than survival for transplant recipients with pri-
posttricuspid shunts had worse survival than those with
mary lung disease.
IPAH. Children with concurrent genetic syndromes and
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genetic background all influence outcomes. Although these trials have yet to include patients with complex
some published cases and short series have raised the congenital heart disease and those with PH after shunt
option of the so-called treat-and-repair strategy,18,102,103 closure. In patients with PH after shunt closure or those
large series with long-term follow-up are still needed to with smaller incident shunts, the use of a reversed Potts
provide criteria to select the patients who benefit most shunt seems a promising alternative to improve quality
from this strategy. of life and survival.108,128 Last, ambulatory extracorporeal
membrane oxygenation as a bridge to recovery in preg-
nant patients with ES before delivery and other adult
FUTURE DIRECTIONS AND RESEARCH patients with PH–congenital heart disease as a bridge
Multiple opportunities exist to improve the care of patients to recovery or lung transplantation may improve overall
with PH–congenital heart disease. From imaging to tai- survival.129,130
lored pharmacotherapy strategies based on anatomical
lesion, the possibilities are limitless. For example, patients
would benefit from the development of an echocardiog- CONCLUSIONS
raphy score that could reduce the number of cardiac PH–congenital heart disease in its various forms car-
catheterizations needed in a lifetime to guide disease ries strikingly different management strategies, is
management. Improvements in cross-sectional cardiac increasingly recognized as a particularly challenging
imaging to refine the evaluation of flow in the pulmo- type of PH to manage, and requires nuanced, expert
nary bed and to assess PVR could serve a similar role. management to improve survival. However, much
In addition, targeted application of artificial intelligence remains unknown about these patients, from the incit-
in cardiac imaging could drive the synthesizing of multi- ing pathophysiology to their optimal management. Ulti-
modality data into meaningful analytics to inform patient mately, understanding the cause and pathophysiology
management. of PH in congenital heart disease within the various
With early diagnosis and management of simple subgroups will allow targeted drug development and
congenital heart disease and prolonged survival of effective treatment strategies. Although great strides
individuals with complex congenital heart disease, the have been made in the management of patients with
paradigm of PH–congenital heart disease has shifted PH in general, as well as those with PH–congenital
toward more complex adult patients whose survival is heart disease, significant gaps remain that demand tar-
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similar to that of patients with IPAH and worse than geted research endeavors. Sustained and committed
that of patients with ES. New insights from randomized multidisciplinary collaboration remains key to reducing
controlled trials using medications for ES have shown the global medical burden caused by pulmonary vascu-
variable but primarily positive results with improvement lar disease associated with congenital heart disease,
in 6-minute walk distance and PVRi.97,125–127 However, the most preventable cause of PH.
Disclosures
Writing Group Disclosures
Writing Other Speakers’ Consultant/
group research bureau/ Expert Ownership advisory
member Employment Research grant support honoraria witness interest board Other
Pei-Ni Jone Lurie Children’s None None None None None None None
Hospital
Usha S. Columbia University Janssen-Actelion None None None None None None
Krishnan Medical Center/New (CUIMC receives
York Presbyterian funding; she has no
Hospital financial benefit. PI for
sponsored research)*;
United Therapeutics
(CUIMC receives fund-
ing; she has no finan-
cial benefit. PI for the
sponsored research)*
Ryan D. Texas Children’s Hos- None None None None None None None
Coleman pital, Baylor College
of Medicine
María Hospital Universita- None None Janssen* None None Ferrer* None
Jesús del rio Ramon y Cajal
Cerro Marín (Spain)
(Continued )
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 $5000 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 $5000 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
Other Speakers’ Consultant/
Research research bureau/ Expert Ownership advisory
Reviewer Employment grant support honoraria witness interest board Other
Catherine Children’s Hospital of Philadelphia/ None None None None None None None
Avitabile University of Pennsylvania
Martin Division of Pediatric Cardiology, None None None None None None None
Koesten- Department of Pediatrics, Grown-
berger Up Congenital Heart Disease Unit,
Medical University Graz (Austria)
Shahin Great Ormond Street Hospital for None None None None None None None
Moledina Children NHS Foundation Trust
(United Kingdom)
Rohit Rao UCSD None None None None None None None
Dietmar Pediatric Heart Center, None None None None None None None
Schranz Johann-Wolfgang-Goethe
University Clinic (Germany)
This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Ques-
tionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $5000 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 $5000 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 10. Zhu T, Chiacchia S, Kameny RJ, Garcia De Herreros A, Gong W,
Raff GW, Boehme JB, Maltepe E, Lasheras JC, Black SM, et al. Mechani-
The American Heart Association makes every effort to avoid any actual or poten- cal forces alter endothelin-1 signaling: comparative ovine models of con-
tial conflicts of interest that may arise as a result of an outside relationship or a genital heart disease. Pulm Circ. 2020;10:2045894020922118. doi:
personal, professional, or business interest of a member of the writing panel. Spe- 10.1177/2045894020922118
cifically, all members of the writing group are required to complete and submit a 11. Fratz S, Geiger R, Kresse H, Roemer G, Hennig M, Sebening W, Hess J.
Disclosure Questionnaire showing all such relationships that might be perceived Pulmonary blood pressure, not flow, is associated with net endothelin-1 pro-
as real or potential conflicts of interest. duction in the lungs of patients with congenital heart disease and normal
This statement was approved by the American Heart Association Science Ad- pulmonary vascular resistance. J Thorac Cardiovasc Surg. 2003;126:1724–
visory and Coordinating Committee on March 14, 2023, and the American Heart 1729. doi: 10.1016/s0022-5223(03)00937-1
Association Executive Committee on April 4, 2023. A copy of the document is 12. Zhu N, Welch CL, Wang J, Allen PM, Gonzaga-Jauregui C, Ma L, King AK,
available at https://professional.heart.org/statements by using either “Search for Krishnan U, Rosenzweig EB, Ivy DD, et al. Rare variants in SOX17 are asso-
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Jone P-N, Ivy DD, Hauck A, Karamlou T, Truong U, Coleman RD, Sandoval JP, del Boldrini R, Stucin-Gantar I, Haass C, Bansal M, et al. Phenotype charac-
Cerro Marín MJ, Eghtesady P, Tillman K, Krishnan US; on behalf of the American terisation of TBX4 mutation and deletion carriers with neonatal and pae-
Heart Association Congenital Cardiac Defect Committee of the Council on Lifelong diatric pulmonary hypertension. Eur Respir J. 2019;54:1801965. doi:
Congenital Heart Disease and Heart Health in the Young; Council on Cardiopulmo- 10.1183/13993003.01965-2018
nary, Critical Care, Perioperative and Resuscitation; Council on Cardiovascular and 14. Arvanitaki A, Gatzoulis MA, Opotowsky AR, Khairy P, Dimopoulos K,
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The expert peer review of AHA-commissioned documents (eg, scientific Del Cerro MJ, Ivy D, Kashour T, Kumar K, Harikrishnan S, et al. Repair of
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AHA Office of Science Operations. For more on AHA statements and guidelines dren: what are the minimal investigative procedures? Consensus statement
development, visit https://professional.heart.org/statements. Select the “Guide- from the Congenital Heart Disease and Pediatric Task Forces, Pulmonary
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tribution of this document are not permitted without the express permission of the 16. Kozlik-Feldmann R, Hansmann G, Bonnet D, Schranz D, Apitz C,
American Heart Association. Instructions for obtaining permission are located at Michel-Behnke I. Pulmonary hypertension in children with congenital heart
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statements-and-policies/copyright-request-form). Paediatric Pulmonary Vascular Disease Network. Heart. 2016;102(suppl
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