REVIEW METHODIST DEBAKEY CARDIOVASC J | 17 (2) 2021

Evaluation and Management of Pulmonary Arterial Hypertension

in Congenital Heart Disease
Hassaan B Arshad, MD; Valeria E Duarte, MD

HOUSTON METHODIST DEBAKEY HEART & VASCULAR CENTER, HOUSTON, TEXAS

ABSTRACT: Pulmonary arterial hypertension is a common complication in patients with congenital heart disease (CHD), aggravating the natural
course of the underlying defect. Pulmonary arterial hypertension (PAH) has a multifactorial etiology depending on the size and nature of the
cardiac defect as well as environmental factors. Although progress has been made in disease-targeting therapy using pulmonary vasodilators to
treat Eisenmenger syndrome, important gaps still exist in the evaluation and management of adult patients with CHD-associated PAH (PAH-CHD)
who have systemic-to-pulmonary shunts. The choice of interventional, medical, or both types of therapy is an ongoing dilemma that requires
further data. This review focuses on the evaluation and management of PAH-CHD in the contemporary era.

INTRODUCTION and obstructive remodeling of the pulmonary vasculature as

well as inflammation and thrombosis.6 Consequently, there is an
The population of adults with congenital heart disease (CHD) increase in pulmonary artery pressure (PAP). If the PAP reaches
has significantly grown over the last few decades thanks suprasystemic values, this can lead to shunt reversal (right-
to advances in cardiac and surgical care.1 This increase to-left shunt) and consequent cyanosis, a condition known as
in the number of patients is accompanied by an increase Eisenmenger syndrome.
in complexity,2 with patients requiring life-long specialized
care and surveillance for complications. Pulmonary arterial CLASSIFICATION OF PULMONARY HYPERTENSION IN CHD PATIENTS
hypertension (PAH) is a well-known complication of CHD.
Population-based studies have reported that between 6% A clinical classification of PAH in CHD was presented during
and 28% of adults with CHD are diagnosed with PAH.3,4 the 5th World Symposium of Pulmonary Hypertension in 2013
We review the clinical implications, pathophysiology, clinical (Table 1).7 This classification separates patients into four clinical
classification, diagnosis, and management considerations in and phenotypical groups. We will follow this classification to
dealing with CHD-associated PAH (PAH-CHD). detail the characteristic of these phenotypes.

CLINICAL IMPLICATIONS 1. Eisenmenger Syndrome

Pulmonary hypertension increases the all-cause mortality Eisenmenger syndrome (ES) is the most severe form of
rate by two-fold and morbidity such as heart failure and PAH-CHD. It is the result of unrepaired, unrestricted
arrhythmia by three-fold compared to patients without PAH. left-to-right shunting that leads to severe PAH. Large
It also increases resource utilization and admissions to unrestricted ventricular septal defects (VSDs) lead to ES
intensive care units. Clinical deterioration has even been more frequently than large atrial septal defects (ASDs).
reported after defect repair in some patients.4,5 Initially, the hemodynamics are characterized by a significant
left-to-right shunt that leads to a progressive increase in PAP
PATHOPHYSIOLOGY due to the combined effect of volume overload and shear
forces that elevate the pulmonary vascular resistance (PVR).
The mechanism behind the development of PAH-CHD is multi- As the PAP approaches the level of systemic pressure, the
factorial. The most frequent cause of PAH-CHD is unrepaired amount of the left-to-right shunt decreases. Once the PVR
shunts, which is the incomplete separation of the pulmonary equals the systemic vascular resistance (SVR), the shunt
and systemic circulation. This leads to unrestricted flow from becomes bidirectional. Finally, when the PVR is higher
the systemic to the pulmonary circulation, with pressure and/ than the SVR, the shunt reverses to right-to-left, leading
or volume overload of the pulmonary circulation that, in turn, to cyanosis and ES (Figure 1).11,12 Chronic cyanosis leads
induces irreversible changes in the medium and small arteries; to erythrocytosis, coagulopathy, thrombocytopenia, and
this inevitably leads to vasoconstriction, endothelial proliferation, clubbing among other clinical features of ES. In these

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defects compared to post-tricuspid shunts. Pre-tricuspid

• Includes all large intra- and extracardiac
defects, which begin as systemic-to- shunts include ASDs, sinus venosus defects, unroofed
pulmonary shunts and progress with time coronary sinus, and anomalous pulmonary vein return
to severe elevation of PVR and to reversal
EISENMENGER SYNDROME
(pulmonary-to-systemic) or bidirectional and cause volume overload of the pulmonary vascular
shunting. Cyanosis, secondary erythrocytosis, bed, with associated enlargement of the right atrium and
and multiple organ involvement are usually
present.
right ventricle. In these patients, the degree and duration
of volume overload tend to be the key determinants of
• Correctable endothelial injury, and the PAP typically does not increase
PAH ASSOCIATED • Noncorrectable
significantly until adulthood.14 Post-tricuspid defects include
WITH PREVALENT • Includes moderate to large defects;
SYSTEMIC-TO-PULMONARY PVR is mildly to moderately increased, VSDs, PDAs, and aortopulmonary window and lead to
SHUNTS systemic-to-pulmonary shunting is still volume and pressure overload of the pulmonary vasculature
prevalent. Cyanosis at rest is not a feature.
and associated dilation of the left ventricle. Unrestrictive
• Marked elevation in PVR in the presence of post-tricuspid defects expose the pulmonary circulation to
small cardiac defects (usually ventricular higher pressures and are more likely to induce early and
septal defects < 1 cm and atrial septal defects
PAH WITH SMALL/ < 2 cm of effective diameter assessed by more severe pulmonary vascular disease, with high-pressure
COINCIDENTAL DEFECTS echo), which themselves do not account for shear forces playing a crucial role. 14,15
development of elevated PVR; the clinical
picture is very similar to idiopathic PAH.
Closing the defects is contraindicated. Notably, patients with Down syndrome develop accelerated
pulmonary vascular disease compared with non–Down-syndrome
• Congenital heart disease is repaired, but PAH
either persists immediately after correction
patients who have similar cardiac defects.16
PAH AFTER DEFECT
or recurs/develops months or years after
CORRECTION
surgery in the absence of significant 3. PAH With Coincidental Congenital Heart Disease
postoperative hemodynamic lesions.

Table 1. This group includes patients with significant elevation in

2013 clinical classification of pulmonary arterial hypertension PVR in the presence of small cardiac defects, which do not
associated with congenital heart disease. This classification explain the degree of PAH. CHD has no causal relationship
remained unchanged in the 6th World symposium of Pulmonary with PAH. This is a similar clinical picture to idiopathic PAH,
Hypertension. Reprinted with permission from Elsevier.7 and it is contraindicated to close the defects. 7
PVR: pulmonary vascular resistance; PAH: pulmonary arterial
hypertension; HCV: hepatitis C virus 4. Postoperative PAH

In these cases, PAH persists, recurs, or develops after

patients, shunt closure is contraindicated because it could surgical repair of the congenital defect. The clinical
lead to acute right ventricular failure and high mortality. phenotype is often aggressive.7

The prevalence of ES has decreased by 50% in the Western OTHER CONGENITAL HEART DEFECTS ASSOCIATED WITH PAH
world due to advances in surgical care for CHD.6 Most
patients who develop ES reach adulthood, with reported In addition to simple shunts, other complex unrepaired conditions
survival between 25 to 75 years in population-based studies.13 are associated with PAH. Examples are unrepaired complete
atrioventricular canal, transposition of the great arteries with a
2. Left-to-Right Shunts VSD, single ventricle physiology with unrestricted pulmonary
flow, and unrepaired truncus arteriosus, among others.
Moderate-to-large, hemodynamically significant systemic-
to-pulmonary shunts may lead to PAH when they are Patients with Fontan Circulation
not repaired. These shunts can be intracardiac, such as
ASDs and VSDs, or extracardiac, such as patent ductus Patients with single ventricle physiology who have undergone
arteriosus (PDA) and aortopulmonary windows. There is a Fontan operation have passive circulation from the systemic
heterogeneity in the hemodynamic consequences depending veins to the pulmonary vasculature. This circulation system
on the location of the shunt, the size of the defect, and the relies on low PVR. Adverse pulmonary vascular remodeling
genetic predisposition. Traditionally, small-to-moderate might play a role in the worsening hemodynamics that patients
lesions are defined as ASD ≤ 2 cm and VSD/PDA ≤ 1 cm; with a Fontan operation experience over time.17 Even though the
large lesions are ASD > 2 cm and VSD/PDA > 1 cm. The PVR may not meet the definition of PAH in these patients, data
pathophysiology of PAH differs in patients with pre-tricuspid suggests that they benefit from treatment to lower the PVR.

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observed with high-flow patients (eg, left-

to-right shunt or pulmonary regurgitation)
because under these circumstances,
PASP increases disproportionally to
mPAP. Right ventricular dysfunction is
common with CHD, even in the absence
of PAH, and consequently does not
reliably identify PAH.

Cardiac Magnetic Resonance

Cardiac magnetic resonance (CMR)

plays a valuable role in assessing RV
size and function because it provides
reproducible and reliable data.20 CMR
Figure 1. has a unique value in the assessment
Pathophysiology of pulmonary arterial hypertension in a patient born with a hemodynamically and serial follow-up of patients with
significant septal defect. Pressure and volume overload of the pulmonary circulation increases the ACHD because it offers unrestricted and
severity of pulmonary vascular resistance, leading to an initial fall and eventual reversal of the shunt. noninvasive access to the heart and great
vessels without the need for ionizing
radiation.10 In the presence of shunt
DIAGNOSIS AND EVALUATION OF PAH TTE can estimate the subpulmonary lesions, we can quantify the net forward
ASSOCIATED WITH CHD ventricular pressure and PAP in the flow through the aortic valve and the
absence of obstructive disease of the pulmonary valve by using phase contrast
Pulmonary hypertension–congenital right ventricular outflow tract (RVOT) technique and thus measure Qp:Qs
heart disease should be suspected in or pulmonary valve using the Doppler noninvasively to assess the hemodynamic
all CHD patients with persistent cardiac velocity across the tricuspid valve. significance of the shunt.
shunt who present with a decline in TTE is also the first step in visualizing
functional status or right heart failure the underlying cardiac anatomy, shunt Cardiac Catheterization
symptoms (lower extremity edema, defect size, and pressure gradient
abdominal distention, exertional syncope, to determine (1) if the anatomy is All symptomatic patients with PAH
weight gain). Most commonly, PAH-CHD restrictive, (2) the level and direction must undergo cardiac catheterization
comes to attention when estimated of shunting, and (3) ventricular size with shunt evaluation to confirm the
PAP is found to be elevated on routine and function.6,19 Detection of an intra- diagnosis of PAH, delineate the underlying
echocardiographic assessment.10 A or extracardiac shunt may present a pathophysiology, determine the prognosis
comprehensive diagnosis and evaluation challenge when there is equalization and response to therapy, and evaluate
are warranted for all patients with of pressures between chambers and candidacy for operative/device closure
suspected PAH-CHD. The following bidirectional shunting. in patients with shunt physiology.10,21
focuses on critical diagnostic tests Confounders such as pulmonary artery
including echocardiography, cardiac Pulmonary arterial hypertension is or pulmonary vein stenosis should be
magnetic resonance imaging, and often suspected based on elevated excluded during an invasive assessment.6
cardiac catheterization, all of which are tricuspid regurgitation peak velocity, Catheterization data is a snapshot of
helpful in making the diagnosis, defining which indicates elevated right ventricular the resting hemodynamics at a single
the pathophysiology, evaluating the systolic pressure (RVSP). Caution must moment in time. Dynamic maneuvers,
candidacy for either surgical or medical be exercised in the CHD population such as inhaled nitric oxide challenge,
management, and evaluating prognosis because, in the presence of RVOT volume loading, and exercise, will help
and response to therapy.18 obstruction, elevated RVSP does not determine the prevailing pathophysiology
correlate with elevated pulmonary artery in borderline or mixed PAH cases.18
Echocardiography systolic pressure (PASP)18,19; PASP Obtaining accurate pulmonary artery and
estimations must therefore account for vein saturations is not a trivial task for
Transthoracic echocardiogram (TTE) any RV outflow gradient. In addition, CHD patients with any level of complexity.
is the preferred imaging modality to PASP correlates with mean PAP (mPAP), Even appropriately collected accurate
screen for PAH in patients with CHD. which means that caution must also be data can unknowingly be misleading. As

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such, catheterization should be performed by an experienced (Qp:Qs ≥ 1.5:1) is considered in patients with symptoms and
ACHD specialist.10 ventricular dilation provided that the systolic PAP is less than
50% of the systolic systemic pressure and the PVR is less than
MANAGEMENT OF PAH IN CONGENITAL HEART DISEASE one-third of the SVR.10 Closure of defects in the presence of
severe PAH (PAP > two-thirds systemic; PVR > two-thirds
Given that PAH-CHD is a very heterogeneous population that of the SVR in the AHA/ACC guidelines and PVR > 5 WU in
has been excluded from randomized clinical trials for pulmonary the European guidelines) and/or a net right-to-left shunt is
hypertension, the management guidelines are based mainly on contraindicated.9,10 This is based on the increased mortality
clinical expertise rather than a strong level of evidence.9,10,22,23 after closure in patients with the described hemodynamics.25

Supportive Management Patients who do not meet the hemodynamic cutoff for
intervention are in the “therapeutic gray zone” for defect repair.
It is recommended that patients with PAH-CHD be assessed The AHA/ACC guidelines recommend that these patients be
by a physician trained in ACHD. Pregnancy in this setting is evaluated by an ACHD and PAH team to treat PAH before
associated with high maternal and fetal mortality, thus reliable consideration for closure. The 2020 European Society of
contraception should be established to avoid pregnancy. Regular Cardiology guidelines for the management of ACHD have given
immunization with influenza and pneumococcal infections a class IIB indication for fenestrated closure of septal defects
should be ensured. Appropriate diuresis should be instituted in patients with severe PAH when the PVR falls below 5 WU
in patients exhibiting signs and symptoms of right heart failure. after targeted PAH treatment and a significant left-to-right shunt
Patients with indications for anticoagulation (those with atrial is present.9 However, given the lack of established markers of
fibrillation, mechanical valves, or pulmonary embolism) should favorable prognosis in this group, decisions should be based
receive it unless there are contraindications.23 Anticoagulation in on the patient's careful clinical and hemodynamic evaluation.
the absence of atrial arrhythmia, mechanical valves, or vascular Assessment of such patients should be performed in tertiary
prosthesis is not generally recommended in PAH-CHD and care centers with expertise in ACHD and PAH.23
should be decided on an individual basis.9 History of hemoptysis
should be carefully assessed before initiation of anticoagulation. Eisenmenger Syndrome

Disease-Targeting Therapy The management of patients with ES is limited to palliative

measures and heart and lung transplantation for eligible
The mainstay of treatment in PAH-CHD is targeted PAH therapy, patients.12 Recent advances in management have focused on
which works best when started early.24 Targeted PAH therapy improving the quality of life of these patients. Adult patients
includes three classes of substances: (1) endothelin receptor with ES should be closely monitored and managed by ACHD
antagonists (ERAs), (2) phosphodiesterase type 5 (PDE-5) specialists. 10 Supportive measures include maintaining
inhibitors, and (3) prostanoids. The ultimate aim of therapy is to hydration, treating iron-deficiency anemia, establishing
attain reasonable or appropriate exercise ability and quality of life contraception and avoiding pregnancy, and antiarrhythmic
and enhance or sustain ventricular function.22 therapy. Routine phlebotomy is contraindicated because
it may impair oxygen transport capacity, reduce exercise
PAH-CHD With Coincidental Defects or PAH After Defect tolerance, induce iron deficiency, and increase the risk
Closure of stroke. 6,26 Phlebotomy should be reserved to relieve
hyperviscosity syndrome and should be accompanied by
The pathophysiology of this group is similar to patients appropriate volume replacement. Routine anticoagulation has
with idiopathic PAH and should be treated as such. Defect not been shown to increase survival. Anticoagulation is only
closure in these patients is contraindicated.16 Treatment suitable in patients with another indication of anticoagulation
includes targeted PAH therapy, with lung or heart-lung in the absence of clinically significant hemoptysis.27
transplantation reserved for deteriorating symptoms despite
maximized oral and intravenous therapy. In the BREATHE-5 trial (Bosentan Randomized Trial of
Endothelin Antagonist Therapy-5), bosentan showed improved
PAH With Systemic-to-Pulmonary Shunt exercise capacity (6-minute walk distance) and hemodynamics
(mPAP and PVR index) in patients with New York Heart
The 2018 American Heart Association (AHA)/American College Association class III symptoms with ES.28 Current clinical
of Cardiology (ACC) Guidelines for the Management of Adults guidelines recommend initiating bosentan as a first-line therapy
with Congenital Heart Disease recommend that surgical or (class I) in symptomatic adults with ES.10 Combination therapy
percutaneous closure of hemodynamically significant defects with PDE-5 inhibitors is indicated (class IIa) in patients with

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Figure 2.
Trials specific to pulmonary arterial hypertension therapy done in patients with congenital heart disease, specifically in those with Eisenmenger syndrome (ES)
and with single ventricle physiology and Fontan operation.28,29,35-38

suboptimal responses to bosentan and the pulmonary arteries in patients with (class IIa).10 Figure 2 shows clinical
has been shown in smaller trials to be single ventricle physiology without a trials evaluating PAP therapy in patients
beneficial for exercise capacity.29 subpulmonic ventricle. As such, the with congenital heart disease, including
There is limited data on prostanoids; circulation is passive and dependent ES, single ventricle physiology, and
typically, continuous intravenous on low pulmonary pressures. 23 Even Fontan operation.
infusions are not routinely prescribed due a slight rise in mPAP or PVR will
to the risk for infection and paradoxical lead to a failing Fontan circulation. 33 CONCLUSION
embolism.30 Other agents have not Because maintaining a low PVR is vital
shown consistent benefit.31 to the viability of Fontan circulation, Recent advances in diagnosis and
PDE-5 inhibitors have been viewed management have significantly improved
Most centers adopt a symptom-oriented as an appealing option for patients survival in the CHD population. Timely
care plan for ES, usually beginning with with high Fontan pressures and have repair of hemodynamically significant
an ERA or PDE-5 inhibitor and escalating been shown to improve cardiac output shunts remains the cornerstone of
to combination therapy for persistent and functional capacity in Fontan therapy. Patients with significant shunts
symptoms or in the event of clinical patients.34-36 In the FUEL (Fontan who have already developed PAH should
worsening. Patients with ES who receive Udenafil Exercise Longitudinal) trial, be evaluated and treated at a center with
disease-targeted therapy have better udenafil did not show an increase in ACHD and PAH expertise. Patients who
survival compared with those not on peak oxygen consumption but did show develop ES have increased morbidity
targeted therapies.32 improvement in measures of exercise and mortality. There is growing evidence
performance. 37 The use of ERAs has of the benefits of pulmonary vasoactive
Management of PAH in Fontan Patients shown benefit in exercise capacity. 38 agents in patients with ES and Fontan
The clinical guidelines recommend circulation. Pregnancy remains a high
A Fontan operation redirects the the use of pulmonary vasoactive risk in this patient population, and timely
superior and inferior vena cava flow to medications in Fontan patients contraception counseling is indicated.

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6. Diller GP, Dimopoulos K, Kaya MG, et al. Long-term safety, tolerability

KEY POINTS and efficacy of bosentan in adults with pulmonary arterial hypertension
associated with congenital heart disease. Heart. 2007 Aug;93(8):974-6.
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center with ACHD and PAH expertise. Pulmonary Hypertension: what’s old is new. F1000Research. 2019 Jun
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Management of Adult Congenital Heart Disease 2020. Eur Heart J. 2020 Nov
Corresponding Author: 14;41(43):4153-4154. doi: 10.1093/eurheartj/ehaa701.
vduarte@houstonmethodist.org
10. Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC Guideline for
Conflict of Interest Disclosure: the Management of Adults With Congenital Heart Disease: A Report
The authors have completed and submitted the Methodist DeBakey of the American College of Cardiology/American Heart Associa-
Cardiovascular Journal Conflict of Interest Statement and none were reported. tion Task Force on Clinical Practice Guidelines. Circulation. 2019 Apr
9;139(14):e698-e800. doi: 10.1161/cir.0000000000000603.
Keywords:
pulmonary arterial hypertension; PAH pathways; pulmonary hypertension 11. Arvanitaki A, Giannakoulas G, Baumgartner H, Lammers AE. Eisenmenger
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