386

STATE OF THE ART ARTICLES

Pulmonary Regurgitation after Tetralogy of Fallot Repair: Clinical

Features, Sequelae, and Timing of Pulmonary Valve Replacement

Naser M. Ammash, MD,* Joseph A. Dearani, MD,† Harold M. Burkhart, MD,† and
Heidi M. Connolly, MD*
Divisions of *Cardiovascular Diseases and Internal Medicine, and †Cardiovascular Surgery, Mayo Clinic, Rochester,
Minn, USA

ABSTRACT

Pulmonary regurgitation following repair of tetralogy of Fallot is a common postoperative sequela associated with
progressive right ventricular enlargement, dysfunction, and is an important determinant of late morbidity and
mortality. Although pulmonary regurgitation may be well tolerated for many years following surgery, it can be
associated with progressive exercise intolerance, heart failure, tachyarrhythmia, and late sudden death. It also often
necessitates re-intervention. Identifying the appropriate timing of such intervention could be very challenging given
the risk of prosthetic valve degeneration and the increased risk of reoperation. Comprehensive informed and regular
assessment of the postoperative patient with tetralogy of Fallot, including evaluation of pulmonary regurgitation,
right heart structure and function, is crucial to the optimal care of these patients. Pulmonary valve replacement
performed in an experienced tertiary referral center is associated with low operative morbidity and mortality and
very good long-term results. Early results of percutaneous pulmonary valve replacement are also promising.

Key Words. Tetralogy of Fallot; Pulmonary Regurgitation; Congenital Heart Disease

Introduction ventriculotomy, and infundibulectomy as well as

generous transannular patching of the RV outflow
S urgical repair of tetralogy of Fallot (TOF)
has been successfully performed since 1955.
Repair includes closure of the ventricular septal
tract; all of these techniques were routine surgical
practice for TOF repair in the past.4 It has detri-
defect, and relief of right ventricular (RV) outflow mental long-term effects on RV size and function,
tract obstruction that involves RV outflow tract and has a recognized impact on late outcome. It
infundibular muscle resection, pulmonary valvo- is anticipated that with increasing recognition of
tomy or valvectomy, and commonly RV outflow the detrimental impact of chronic PR, the rate of
augmentation with placement of a subvalvular or PV replacement will continue to increase and the
transannular patch. The long-term outcome timing of intervention will be refined.5,6
reported following surgical repair of TOF is excel-
lent with survival rate of 86% at 30 years.1 Despite
Determinants of PR
the profound impact of surgical intervention on
functional status, survival, and quality of life,2 The degree of PR after TOF repair is determined
postoperative residua and sequelae are expected in by many anatomic and hemodynamic factors
patients with repaired TOF and lifelong informed (Table 1).7,8 In patients with TOF, the pulmonary
follow-up is required.3 valve (PV) is usually abnormal, often bicuspid, may
Chronic pulmonary valve regurgitation (PR) is be hypoplastic or absent (2%). Tetralogy of Fallot
the most common cardiovascular sequela requir- with absent PV presents early in life with massive
ing reoperation in patients with repaired TOF. enlargement of the pulmonary arteries due to
It is most commonly associated with extensive severe PR, and is not included in this discussion.
© 2007, the Authors
Congenit Heart Dis. 2007;2:386–403 Journal compilation © 2007, Blackwell Publishing, Inc.
Tetralogy of Fallot 387

Table 1. Determinant of Pulmonary Regurgitation and severity of tricuspid valve regurgitation; and
• Residual pulmonary valve abnormality (5) the presence of a residual shunt at atrial or
• Hypoplastic ventricular level.
• Absent valve Reduced RV systolic function is common after
• Postpulmonary valvotomy/valvectomy
• Transannular patch repair repair of TOF and is related to: (1) the degree and
• Right ventricular outflow tract aneurysm duration of preoperative cyanosis; (2) the degree
• Right ventricular diastolic dysfunction and duration of preoperative pressure overload
• Pulmonary annulus size
• Peripheral pulmonary artery stenosis with resultant RV hypertrophy; (3) tricuspid and
• Pulmonary vascular resistance PR; (4) residual RV outflow obstruction; (5) RV
• Residual atrial and ventricular septal defects injury at the time of surgery from the right ven-
• Acquired cardiovascular and pulmonary diseases
• Pulmonary hypertension triculotomy and resection of RV muscle bundles;
• Sleep apnea (6) placement of the a noncontractile RV outflow
• Hypertension patch, and ventricular septal defect patch; and (7)
• Chronic lung disease
• Kyphoscoliosis potential interruption of coronary artery supply
related to disruption of an anomalous coronary
artery or inadequate myocardial preservation at
the time of operation.6 Histopathological studies
Tetralogy of Fallot after repair is often associ- have demonstrated irreversible RV myocardial
ated with an altered geometric orientation of the damage leading to RV systolic and diastolic dys-
branch pulmonary arteries, unequal pulmonary function after TOF repair.6
vascularity, and pulmonary perfusion abnormali- Davlouros et al.11 demonstrated that RV hyper-
ties that contribute to PR.9 The state of pulmonary trophy, outflow tract aneurysm, and akinesis were
arteriolar bed, pulmonary vascular resistance all associated with lower RV ejection fraction in
including compliance of the vessel wall, airway patients with repaired TOF. Contractile dysfunc-
pressure, venous resistance, and left atrial pressure tion was not found to be related to the use of an
may also influence the pulmonary blood flow outflow patch, raising the concern that factors
pattern and PR. Chaturvedi et al.10 showed that a such as myectomy, infundibulectomy, and
small increase in airway pressure led to increased ischemic insult are in part responsible for the
total PR presumably because of subtle changes in genesis of RV outflow tract akinesis in patients
pulmonary vascular resistance. Transannular patch who did not have a patch.
enlargement and aggressive infundibulectomy are Babu-Narayan et al.15 demonstrated the pres-
known to predispose to RV outflow tract aneurysm ence of myocardial fibrosis using gadolinium
that adversely affects the RV and PR severity.11–14 enhancement during cardiac magnetic resonance
(CMR). Areas of myocardial fibrosis were seen in
Complications of PR regions of surgical resection, patch placement,
suturing, or vent insertion, as well as areas remote
Chronic severe PR results in progressive RV from surgical instrumentation in trabecular and
enlargement, systolic and diastolic dysfunction, endocardial fibers of the RV that may be more
and eventually progressive tricuspid valve regurgi- vulnerable to ischemic insult. Patients with more
tation. Patients may be asymptomatic for many severe fibrosis were older, had more RV dys-
years but may eventually present with fatigue, function, exercise intolerance, and clinical
dyspnea, exercise limitation, atrial or ventricular arrhythmias.
tachyarrhythmia, and occasionally sudden death. Right ventricular diastolic dysfunction has been
Some patients tolerate severe PR better than a concern in repaired TOF, and may be related to
others. This implies that the duration and severity all the factors associated with RV systolic dysfunc-
of PR are not the only factors causing progressive tion. Diastolic dysfunction is particularly common
clinical deterioration. in TOF patients after transannular patch place-
ment. In a study by Munkhammar et al.,16 47
RV Enlargement and Dysfunction patients with repaired TOF were evaluated by
The RV adaptive response to volume overload echocardiography. Restrictive RV physiology was
from PR depends on: (1) the duration and the noted in 13 patients (28%). Ten percent of patients
degree of the PR; (2) the properties of the RV; (3) repaired before 6 months of age demonstrated
the status of the pulmonary arteries and the pres- restrictive features at the time of follow-up,
ence of pulmonary hypertension; (4) the presence increasing to 38% with repair after 9 months.
Congenit Heart Dis. 2007;2:386–403
388 Ammash et al.

Approximately one third of patients with transan- gram, Holter monitor, and electrophysiology
nular patch repair demonstrated restrictive testing for sustained ventricular tachycardia or
hemodynamics. The patients with restrictive sudden death is low.7,8
hemodynamics had more severe preoperative pul- Right ventricular dilatation slows ventricular
monary stenosis, were older at the time of TOF activation and intraventricular conduction and
repair, and had less severe PR on follow-up. Right creates a mechanoelectrical substrate for re-entry
ventricular diastolic dysfunction with elevation in circuits and may serve as an arrhythmogenic
RV diastolic pressure limits the duration of PR and trigger. Gatzoulis et al.18 demonstrated that PR
the degree of RV dilatation. As a result, patients was the most common cardiovascular hemody-
with restrictive RV physiology have smaller RV namic abnormality noted in a group of patients
volume.5,8,13,16 who developed ventricular tachycardia, sudden
As the RV dilates in response to PR, its ejection death, or atrial arrhythmia. Helbing et al.19
fraction initially increases related to the volume reported that the mean QRS duration correlated
overload. With time, the RV ejection fraction significantly with RV volume and mass, LV volume
decreases as a reflection of a decrease in myocar- and mass, percent of PR, and age. This study sug-
dial performance of the volume-loaded RV. gests that QRS prolongation may be a surrogate
Progressive deterioration of myocardial function risk factor for ventricular arrhythmia. A maximum
finally results in decreased stroke volume and QRS duration of ⱖ180 milliseconds or rate of
increased RV end systolic volume. change of >3.5 ms/y has been shown to be a sen-
sitive and relatively specific marker for sustained
Left Ventricular Dysfunction ventricular tachycardia and sudden death in
repaired TOF.20 Perloff et al. have demonstrated
Although the left ventricle (LV) is not directly
that the presence of late potentials on the signal
involved in the anatomic defects of TOF, patients
average electrocardiogram in repaired TOF
who have had previous TOF repair are at risk of
patients also connotes an increased risk for ven-
developing LV dysfunction. Factors that are
tricular arrhythmias.21
known to contribute to the development of LV
Atrial tachyarrhythmias, especially flutter and
dysfunction include: (1) the duration of preopera-
fibrillation, are relatively common following TOF
tive cyanosis; (2) volume overload from a previ-
repair, and have been reported in up to one third
ously placed systemic-to-pulmonary artery shunt;
of adult patients.5 Pulmonary valve regurgitation,
(3) suboptimal myocardial protection during
RV outflow obstruction, tricuspid valve regurgita-
cardiopulmonary bypass; (4) the duration of car-
tion, residual shunts, and surgical scars in the right
diopulmonary bypass itself; (5) patching of the
atrium and septum are known predisposing factors
ventricular septum; (6) myocardial fibrosis; and
that slow conduction promoting re-entry atrial
(7) aortic valve regurgitation secondary to aortic
tachyarrhythmias.
root enlargement.15 Furthermore, Geva et al.17
have suggested that LV dysfunction could be
partly due to the abnormal septal motion and Assessment of Repaired TOF Patients with PR
its detrimental effects of LV geometry and
Assessment of patients following repair of TOF
mechanical performance reflecting unfavorable
should include a thorough medical history, and
ventricular/ventricular interaction.
clinical examination. The surgical report is an
important part of follow-up evaluation in all
Arrhythmias patients with repaired congenital heart disease and
Pulmonary valve regurgitation predisposes TOF should be requested in all patients. Subsequent
patients to atrial and ventricular arrhythmias pri- testing should include electrocardiogram, chest
marily because of the progressive enlargement of radiograph, transthoracic echocardiogram, exer-
the right atrium and ventricle. cise test for assessment of functional status,
Malignant ventricular arrhythmias occur in and a baseline CMR. Select patients require
approximately 0.5–6% of repaired TOF patients. cardiac catheterization to delineate anatomy and
However, the presence of premature ventricular hemodynamics.
beats and nonsustained ventricular tachycardia Pulmonary regurgitation is usually tolerated for
does not identify patients at high risk for sudden many years. Graham et al. reported that symptoms
death. The predictive value of electrocardio- progressively increase after age 30 and that 50%
graphic changes, signal average electrocardio- of patients are symptomatic by age 49 years.22
Congenit Heart Dis. 2007;2:386–403
Tetralogy of Fallot 389

Adverse effects of PR may be missed if the evalu- Center to document exercise capacity and identify
ation depends on history and physical examination changes in functional status over time in patients
alone. Marked RV enlargement and dysfunction followed serially. There are no data demonstrating
can be present before the onset of symptoms. In that PV replacement performed for decline in
our experience, dyspnea, fatigue, palpitations, exercise tolerance improves patient outcome. In
clinical arrhythmias, and poor exercise tolerance addition, comorbidities may affect results of exer-
are often the initial findings in patients with severe cise testing. Thus, results of exercise testing alone
PR. are not used as the primary indication for PV
The cardiovascular examination in repaired replacement in TOF patients with PR, but are
TOF with severe PR may demonstrate prominent used in conjunction with other data to help define
jugular venous pulsation with an increased jugular optimal timing of operation. Wessel et al. showed
venous “a” wave suggesting elevation in the right that exercise performance was 82 ⫾ 21% of pre-
atrial pressure, while a prominent “v” wave sug- dicted in male TOF patients in comparison with
gests associated tricuspid valve regurgitation. control and that the degree of dysfunction was
Right ventricular volume overload is suspected related to cardiomegaly on chest X-ray.23 Carvalho
when an RV heave is present. The first heart sound and coworkers showed significantly reduced dura-
is usually normal followed by a loud single second tion of exercise and negative correlation between
heart sound from the aortic valve. Typically, there exercise time and the degree of PR.24 Important
is no pulmonary component of the second heart contributors to exercise intolerance include
sound as pulmonary valvectomy or valvotomy is comorbidities such as lung disease, and chronotro-
performed during surgical repair. The degree of pic incompetence.8,25
PR can be difficult to ascertain by physical exami- There is interest in the role of brain natriuretic
nation. A to-and-fro murmur in the pulmonary peptide in the assessment of patients with PR after
area reflects systolic and diastolic flow across the TOF repair. Brili et al.26 reported on 25 adults
RV outflow tract. The diastolic murmur of PR is with repaired TOF with PR and 25 healthy con-
best heard with the bell of the stethoscope along trols. Patients with repaired TOF had a signifi-
the left sternal border and is low frequency. A cantly higher brain natriuretic peptide level than
pansystolic murmur noted along the left sternal control, and the increased level correlated with RV
border that increases with inspiration suggests tri- to LV diameter ratio. Furthermore, Ishii et al.27
cuspid valve regurgitation. Signs of RV failure examined the relation between brain natriuretic
include elevated jugular venous pressure, edema, peptide and RV contractile reserve during exer-
hepatomegaly (pulsatile when associated with tri- cise. Plasma brain natriuretic peptide levels were
cuspid valve regurgitation), and ascites. These significantly higher in patients with TOF than in
findings are uncommon unless severe tricuspid controls. Exercise was associated with increased
valve regurgitation or RV dysfunction coexists. plasma brain natriuretic peptide levels in both
Right bundle branch block is almost universally groups. However, a larger increment in brain
present in patients who have had TOF repair via a natriuretic peptide was noted in patients with
right ventriculotomy, and is accompanied by left TOF than in normal subjects. Therefore, exercise-
anterior hemiblock in up to 9–15% and less fre- induced changes in plasma concentration of brain
quently left posterior hemiblock (Figure 1). natriuretic peptide may reflect RV contractile
The chest radiograph in TOF patients with reserve in patients with TOF, and could poten-
severe PR often demonstrates findings of RV tially be used in the assessment of asymptomatic
volume overload with retrosternal fullness on the patients with severe PR to determine the need for
lateral view, and increased cardiothoracic ratio. A PV replacement.
right-sided aortic arch is present in 20–30%
(Figure 1). Patients with a cardiothoracic ratio of
Echocardiography
less than 0.5 are unlikely to have marked RV
enlargement. The chest radiograph may also dem- Transthoracic echocardiography is still the most
onstrate a dilated RV outflow tract, and central commonly used primary noninvasive imaging
pulmonary arteries, and may demonstrate dilata- modality in the assessment of patients with
tion of the ascending aorta. congenital heart disease. A comprehensive
Given the concerns about adaptability and the 2-dimensional (2-D) and Doppler transthoracic
lack of reported symptoms in TOF with severe echocardiographic assessment following TOF
PR, exercise testing is routinely performed at our repair is routinely performed and should include
Congenit Heart Dis. 2007;2:386–403
390 Ammash et al.

Figure 1. (A) Twelve lead electrocardiogram in a patient with severe pulmonary valve regurgitation following tetralogy of
Fallot repair demonstrating right bundle branch block with QRS prolongation of 206 milliseconds and left posterior hemiblock.
(B) The chest radiograph on the same patient demonstrates significant cardiomegaly with features of right heart enlargement
and a right-sided aortic arch (arrow).

Congenit Heart Dis. 2007;2:386–403

Tetralogy of Fallot 391

A
A

Figure 2. Parasternal short axis transthoracic echocardio-

graphic images demonstrating diastolic color flow Doppler
in the right ventricular outflow tract. The red jet represents
the regurgitant pulmonary flow with (A) mild and (B) severe
regurgitation (arrows). Notice the difference in the width of
the color flow jet.

assessment of (1) residual pulmonary stenosis, its

level, cause, and severity; (2) possible cause(s) and
severity of PR; (3) RV size and function; (4) pres-
ence and severity of tricuspid regurgitation; (5) RV Figure 3. Continuous wave Doppler signal at the level of
systolic and pulmonary artery pressure; (6) pres- the pulmonary valve in a patient with mild pulmonary valve
ence of residual atrial or ventricular septal defect; regurgitation demonstrates normal systolic forward flow and
and (7) LV size and function, and also should reversed flow that continues throughout diastole indicating
include the measurement of aortic root and ascend- mild pulmonary valve regurgitation. The low end diastolic
velocity (A) suggests normal pulmonary artery diastolic
ing aorta diameter, and the determination of the pressure. In patients with (B) severe pulmonary regurgita-
presence and severity of aortic valve regurgitation. tion the regurgitant diastolic velocity (arrow) peaks early
Severe PR may cause pulsation in the pulmo- and decreases rapidly as the pulmonary artery to right ven-
nary arteries that extend to the branches accom- tricular pressures rapidly equilibrate, leading to early termi-
panied by abnormal color flow and spectral nation of the continuous wave Doppler signal.
Doppler examination of the RV outflow tract
(Figures 2 and 3). The degree of PR is classified that PR severity could be assessed using a PR area
according to the degree of retrograde diastolic index defined as the maximum area of the PR color
flow into the main pulmonary artery and branch jet in the parasternal short axis imaging plane
pulmonary arteries. Kobayashi et al.28 reported indexed to body surface area. This index was found
Congenit Heart Dis. 2007;2:386–403
392 Ammash et al.

to correlate well with regurgitant fraction deter-

mined by angiogram. However, this technique is
dependent on the direction of the PR jet, machine
gain settings, transducer frequency, and other
patient related issues. Williams et al.29 suggested
using linear measurements rather than area mea-
surements. He demonstrated that the severity of
PR can be determined by the ratio of PR color
jet width to PV annulus in early diastole. A jet/
annulus ratio of 0.7 separated patients with 2+
from those with 3+ angiographic PR.
Poor acoustic windows in patients with previous
operation can limit the ability of accurate mea-
surement of the jet/annulus ratio as well as the
color flow Doppler assessment in the branch pul-
monary arteries. As a result, other echocardio- Figure 4. Assessment of right ventricular diastolic function
in patients with pulmonary regurgitation following tetralogy
graphic methods have been suggested for the of Fallot repair is an integral part of any comprehensive
assessment of the severity of PR using spectral echocardiographic evaluation. Restrictive physiology leads
and continuous wave Doppler. Spectral Doppler to antegrade forward flow in the pulmonary artery (arrow)
assessment at the level of the PV in patients with during atrial contraction. This should be noted during all
less than severe PR demonstrates normal forward phases of respiration and on 5 consecutive beats.
flow in systole and reversed flow in diastole
(Figure 3), the latter representing PR. The dias- regurgitant orifice by color Doppler technique
tolic flow reversal is holodiastolic and its peak such as proximal isovelocity surface area (PISA);
velocity is <1 m/s in the absence of pulmonary (2) measurement of regurgitant volume and re-
hypertension. In patients with severe PR gurgitant fraction as well as effective regurgitant
(Figure 3), the regurgitant diastolic velocity peaks orifice by 2-D and Doppler echo such as continuity
early and decreases rapidly as the pulmonary equation; and (3) measurement of the vena con-
artery–RV pressure difference rapidly equilibrates, tracta. Finally, although the PISA method appears
leading to early termination of the pulsed or to be the most reliable method to assess regurgitant
continuous wave Doppler signal. This is a very volume, this method has not gained widespread use
common Doppler finding of severe PR but can in PR because the assumption of hemispheric shape
also occur in patients with RV diastolic dysfunc- is not valid in most cases of PR in which flow rates
tion due to an elevation in RV end diastolic and trans-orifice pressure gradients are low.
pressure. In restrictive physiology there is early Patients with repaired TOF and PR can also
termination of the Doppler PR signal and presys- have residual PV, infundibulum, or pulmonary
tolic forward flow (Figure 4), differentiating artery branch stenosis. Obstruction can generally
restrictive RV physiology from isolated severe PR. be assessed using continuous wave Doppler
Li et al.30 suggested that the PR index, the ratios technique.
of the duration of the continuous wave Doppler Assessment of the RV size and function is an
PR signal to total diastole, could be measured and integral part of any echocardiographic evaluation.
the ratio between the two correlated closely with Most quantitative 2-D echocardiographic mea-
CMR-derived regurgitant fraction. A PR index of surements of ventricular size and performance are
<0.77 had a 100% sensitivity, and 85% specificity based on geometry assumptions that do not apply
for identifying PR fraction of >24.5%, with a pre- to the RV. The RV has a complex shape. It has a
dictive accuracy of 95%. In a different study, using thinner wall and coarse trabeculations that make
the PR velocity profile by continuous wave endocardial border delineation challenging. In our
Doppler, the pressure half-time was measured and practice, we rely heavily on quantitative assess-
found to be inversely related to PR fraction.31 A ment and side-by-side comparison is used to assess
pressure half-time of less than 100 milliseconds RV size and function serially. Three-dimensional
was found to be a good indicator of severe PR. echocardiography promises accurate determina-
Additional echocardiographic techniques for the tion of RV volume and function; this technique is
assessment of severity of PR include: (1) currently time-consuming and not widely used
measurement of regurgitant volume and effective clinically.
Congenit Heart Dis. 2007;2:386–403
Tetralogy of Fallot 393

Indirect information about RV systolic and and diastole permits direct and accurate measure-
diastolic function is available by conventional ment of RV volume and function. In addition,
Doppler indices. The most commonly used phase-contrast CMR provides a method of evalu-
echocardiographic parameters that have been sug- ation of velocity, volume, and the pattern of blood
gested for the assessment of RV function include: flow that would allow accurate mapping and mea-
(1) Doppler assessment of instantaneous rate of surement of both systolic and diastolic pulmonary
pressure increase (dP/dt); (2) right-sided index of artery flow and calculation of PV regurgitation
myocardial performance (Tei index); (3) Doppler fraction (Figure 5).9,40–42
tissue imaging at the tricuspid annulus; and (4) Baseline CMR is recommended in many con-
strain and strain rate imaging.26,32–38 All these genital heart centers for asymptomatic patients
methods have been used in assessing RV function with repaired TOF in whom echocardiographic
in patients with PR following TOF repair. assessment of RV size and function, or other
Changes in loading conditions may impact some cardiac anatomy is suboptimal. In addition, peri-
of these measurements. Recently, a new easily odic comparison CMR should be considered in
reproducible Doppler measurement of systolic select asymptomatic TOF patients to reassess RV
RV contractile function that is less dependent size and function (Figure 5) in an effort to aid in
on loading conditions has been suggested. The determining the most appropriate timing of inter-
isovolumic acceleration index is calculated by vention for PR.
dividing myocardial velocity during isovolumic Right ventricular volume calculation using
contraction by the time interval from the onset of CMR correlates well with volume as measured by
the acceleration to the time at peak velocity.39 Fri- angiography.43,44 The inter- and intraobserver
giola et al. reported that this index is useful in variability is 5–15%. This is caused by the complex
detecting early preclinical ventricular dysfunction geometry of the RV, the difficulties in defining the
before the onset of symptoms and thus determines correct tricuspid valve plane, difficulty with delin-
appropriate timing of pulmonary valve replace- eation of RV endocardial borders especially in the
ment before significant RV dysfunction occurs.39 presence of an RV outflow aneurysm, increased
Many of these echo-Doppler methods for assess- trabeculation, and the presence of other structures
ment of RV function have been used predomi- such as the moderator band and patches. Using
nantly as research tools; however, their clinical CMR, RV end diastolic and end systolic volumes
application in the future appears promising. are measured, indexed to body surface area,
Assessment of RV diastolic function in patients and compared with normal values (normal RV
with PR following TOF repair is an integral part end diastolic volume = 91 ⫾ 16 cc/m2, RV end
of any comprehensive echocardiographic evalua- systolic = 69 ⫾ 22 cc/m2) to estimate the degree of
tion. Restrictive physiology leads to antegrade RV enlargement. The RV ejection fraction is cal-
forward flow in the pulmonary artery during atrial culated using those measurements with normal
contraction (Figure 4). This antegrade flow is being 61 ⫾ 6%.45
related to abnormal RV compliance, but may be The main concern that had been raised using
present in normal subjects during inspiration and CMR is that it can underestimate the severity of
therefore should be noted in at least 5 consecutive PR when compared with echocardiography. In a
beats.8 study performed by Rebergen et al., only 15% of
the cohorts had a PR regurgitant fraction of more
than 40% whereas a larger proportion of patients,
CMR Imaging
61%, had severe PR by echocardiography.40 It is
Cardiac magnetic resonance has emerged as an the authors’ opinion that the severity of PR is best
accurate and reproducible technique for assessing assessed after a comprehensive evaluation of the
RV volume, function, and PR severity.40,41 Cardiac surgical records to determine the type of operation
magnetic resonance has advantages over echocar- performed in conjunction with echocardiographic
diography; images are not compromised by air, examination as discussed earlier. The use of CMR
bone, or surgical scar allowing unrestricted evalu- to calculate regurgitant fraction is not routinely
ation of RV outflow tract, and the pulmonary used as a clinical tool.
arteries. Multiplane CMR allows direct observa- Gadolinium enhancement during CMR has
tion of RV cavity and its endocardial borders. been used to assess myocardial fibrosis related to
Application of Simpson’s rule for multiple tomo- areas of surgical resection, and patch placement or
graphic slices acquired during ventricular systole other surgical instrumentation may be detected.15
Congenit Heart Dis. 2007;2:386–403
394 Ammash et al.

Figure 5. Phase contrast cardiac magnetic resonance imaging provides an accurate method of evaluation of (A) velocity,
volume, and the pattern of blood flow that allow accurate measurement of both systolic and diastolic pulmonary artery flow
and calculation of pulmonary valve regurgitation fraction. (B) Cardiac magnetic resonance imaging is also a reliable
technique for assessing right ventricular size and function. MPA indicates main pulmonary artery; LV, left ventricle; RV, right
ventricle.

The presence of myocardial fibrosis may have an volume reaches 170 cc/m2 or RV end systolic
impact on patient prognosis; however, additional volume reaches 85 cc/m2. Buechel et al.47 reported
data are required to determine the importance of on children with TOF, severe PR, and RV dilata-
this diagnostic tool. tion who underwent CMR. Pulmonary valve
Several studies have demonstrated the impact of replacement was performed when RV end diastolic
CMR on the assessment of TOF patients with PR. volume exceeded 150 cc/m2. Postoperative RV
Therrien et al.46 noted that in order to improve remodeling with reduction in volume and mass
RV size following PV replacement, operation was observed after PV replacement when preop-
should be performed before the RV end diastolic erative RV end diastolic volume exceeds 150 cc/
Congenit Heart Dis. 2007;2:386–403
Tetralogy of Fallot 395

m2. Right ventricular ejection fraction did not

change significantly. Based on these 2 studies, it
appears that PV replacement should be performed
when the RV end diastolic volume is great than
150 cc/m2 and smaller than 170 cc/m2.

Additional Imaging Techniques

Multislice computerized tomography (CT) scan is
an emerging alternative imaging modality espe-
cially in TOF patients with implantable devices.
However, CT imaging uses ionizing radiation and
older-generation scanners require a low heart rate
for optimal image acquisition. The modern CT
scanners are less sensitive to heart rate for image
acquisition. This technique can also be used to
exclude anomalous coronary artery prior to
reoperation.
Figure 6. Coronary angiography in a 62-year-old woman
Nuclear cardiac imaging at rest and during with repaired tetralogy of Fallot demonstrates anomalous
exercise could also be considered when CMR left anterior descending (LAD) and circumflex artery arising
imaging is not available or feasible. Progressive from the right coronary artery (RCA). The anomalous LAD
RV enlargement and dysfunction and the failure of courses anterior along the right ventricular outflow tract and
the RV ejection fraction to improve with exercise demonstrates an important risk around the time of reopera-
tion. Inadvertent transection of the anomalous coronary
can be used in the evaluation of patients with artery is potentially catastrophic.
repaired TOF and PR. This technique does,
however, have some limitations. Radionuclide
angiography requires the acquisition of views of
intervention, and in patients with suspected
the ventricles that exclude counts from other
anomalous coronary artery to delineate the course
chambers, which can usually be achieved for the
of the coronary artery and outline operative man-
LV but often not satisfactory for the RV.48 In addi-
agement options (Figure 6).
tion, this modality requires an adequate bolus
injection for the first-pass studies and regular
rhythm with a minimal R–R variability. Its resolu-
Arrhythmia Assessment
tion is poor compared with other imaging
methods and therefore has been of limited use Repaired TOF patients have the ideal substrate for
recently.43,48 On the other hand, 123I metaiodoben- ventricular arrhythmias. The aggressiveness of
zylguanidine (MIBG) with tomographic imaging investigation and treatment of ventricular arrhyth-
has been suggested by Daliento et al. as a mean to mias depends on symptoms, underlying structural
analyze the adrenergic nervous system in repaired derangement, and hemodynamic status. Evalua-
TOF.49 tion typically includes electrocardiogram, 24-hour
Cardiac catheterization is only performed Holter monitoring, event monitoring, and at times
in patients when alternative measures cannot signal averaged electrocardiogram, and electro-
accurately assess the RV and pulmonary artery physiology study. The predictive value of pro-
anatomy or hemodynamics noninvasively. Cardiac grammed stimulation for sudden death is unclear
catheterization is performed in patients with sus- in this population, in part because of relatively low
pected pulmonary artery or branch stenosis, and in event rates. A negative electrophysiological study
those suspected of having pulmonary hyperten- may be helpful in the management of these
sion. It is also performed when catheter-guided patients, but a positive study should be interpreted
intervention such as relief of pulmonary artery with caution especially in the presence of hemo-
stenosis is indicated. However, angiographic dynamic abnormalities such as severe PR and RV
evaluation of PR severity is complicated by the fact enlargement.50
that catheter position across the PV may influence Treatment options include antiarrhythmic
the angiographic severity. Coronary angiography medication, radiofrequency ablation, implantable
is performed routinely in adults prior to operative cardiac defibrillator, and arrhythmia surgery.
Congenit Heart Dis. 2007;2:386–403
396 Ammash et al.

These usually should be performed in association Table 2. Indications for Pulmonary Valve Replacement
with repair of the hemodynamic abnormalities Attributable symptoms and signs
such as PR. • Exertional dyspnea
Although correction of the hemodynamic • Exercise intolerance
• Heart failure
abnormalities, such as PR, may be sufficient • Symptomatic or sustained arrhythmias related to right heart
therapy to prevent ventricular tachycardia,51 this enlargement
cannot be reliably predicted. Patients with history Asymptomatic patients with
• Decline in functional aerobic capacity (maximum V0 2) on
of ventricular tachycardia or syncope prior to exercise testing to <70% of gender-age predicted or a decline
planned PV replacement should be considered for >20% compared with serial testing
preoperative electrophysiological study to identify • Progressive RVE and/or dysfunction noted on serial imaging
studies
the mechanism of inducible ventricular tachycar- • Cardiothoracic ratio on chest X-ray
dia, and direct surgical approach to tachycardia • Echocardiogram
intervention if feasible. Scars from prior transven- • CMR
• RV EF <40%
tricular incision and outflow patches are the • Moderate or more tricuspid valve regurgitation related to
ideal anatomic substrate facilitating a re-entrant long-standing PR
rhythm. • TOF patients with severe PR and coexisting cardiac lesions
themselves requiring surgical intervention such as
Therrien et al.52 reported that the freedom • Significant residual shunt
from preexisting clinical arrhythmia at 5 years • RVOT obstruction (RVSP ⱖ2/3 systemic)
with surgical cryoablation was 100% compared • Clinical arrhythmias due to severe PR
• Ventricular arrhythmia prevention
with 68% without concomitant cryoablation at the • QRS ⱖ 180 ms
time of PV replacement in TOF patients. An • QRS prolongation >3.5 ms/y
aggressive approach for surgical treatment of atrial RVE indicates right ventricular enlargement; CMR, cardiac magnetic reso-
and ventricular arrhythmias is routinely followed nance; RV EF, right ventricular ejection fraction; PR, pulmonary valve regur-
gitation; TOF, tetralogy of Fallot; RVOT, right ventricular outflow tract; RVSP,
in our practice. In addition, we would consider a right ventricular systolic pressure.
repeat electrophysiological study after PV replace-
ment and arrhythmia surgery in patients with pre-
operative ventricular arrhythmia to determine replacement is the only treatment modality with
success of the operation or the need for implanta- proven long-term benefit including reduction in
tion of automated defibrillator. However, the RV size, and improvement or at least stabilization
latter could be complicated by inappropriate of RV function.
defibrillator discharges due to atrial arrhythmias
and therefore the benefits of an automated Timing of Pulmonary Valve Replacement
defibrillator should be weighed against potential Pulmonary valve replacement carries a low
complications. operative risk when performed by experienced
and skilled surgeons and leads to restoration of
PV function, symptomatic improvement and
Treatment of PR
improvement of RV size, and stabilization of
Medical therapy for patients with severe PR function when performed at the optimal
following TOF repair is very limited. Diuretics time.1,14,25,46,52–54
are used in patients presenting with edema or Indications for PV replacement are in evolution
symptoms of congestive heart failure. Afterload (Table 2). There is agreement that the presence of
reduction with angiotensin converting enzyme symptoms due to PR is an indication for PV
inhibitor, angiotensin receptor blocker, or beta replacement in TOF patients. However, deter-
blocker has no proven benefit in TOF patients mining timing of intervention in asymptomatic
with PR. TOF patients with PR remains controversial. We
Patients with PR demonstrate features of neu- recommend PV replacement for asymptomatic
rohormonal activation and impaired cardiac auto- TOF patients with severe PR and the following:
nomic nervous system activity and therefore the (1) progressive reduction in exercise tolerance or
use of medications may convey symptomatic ben- important reduction in exercise tolerance related
efits.13 Elevated levels of brain natriuretic peptide to abnormal cardiac output response to exercise;
at rest and with exercise have been demonstrated (2) progressive RV enlargement (>150 cc/m2 by
in patients with PR following TOF repair.26,27 CMR) or RV dysfunction;1,13,22,25,46,52,55 (3) devel-
Although patients may demonstrate some symp- opment of clinical arrhythmias, increased QRS
tomatic improvement with medical therapy, PV duration on the electrocardiogram ⱖ180 millisec-
Congenit Heart Dis. 2007;2:386–403
Tetralogy of Fallot 397

onds or QRS increase ⱖ3.5 ms/y; and (4) progres- experience regurgitation is much more likely with
sive tricuspid valve regurgitation.46,47 the pulmonary homograft. Consequently, if a
homograft is desired and pulmonary hypertension
is present, an aortic homograft is preferred. In the
Pulmonary Valve Replacement
current era, homograft prostheses, limited by the
Despite advances in the development of biopros- available size, are preferred when PV replacement
thesis and homografts, progressive prosthetic is required during infancy and in patients under-
valve deterioration requiring subsequent reopera- going the Ross procedure. The International Ross
tion remains a problem following PV replacement. Registry report of 2610 documented Ross opera-
In addition, there is a small but important surgical tions; freedom from reoperation on the RV
risk. Therefore, appropriate surgical patient selec- outflow tract was 91% at 10 years and 84% at
tion is important. Review of the risks and benefits 25 years.14
of intervention vs. continued observation with its In our practice, we favor porcine or pericardial
inherent risk must be carefully considered. bioprosthesis in children and adults when PV
Isolated PV replacement continues to be a low- replacement is necessary. A pericardial patch is
risk procedure with a perioperative mortality of often used to enlarge the pulmonary annulus, and
1–2% and excellent 10-year survival of 86–95% in proximal pulmonary arteries as needed. This
experienced Adult Congenital Surgical centers, allows the prosthesis to be normal or slightly over-
even in the presence of multiple reopera- sized, which may be especially important when
tions.5,12–14,55–58 The operative risk increases with there is significant RV dysfunction. In our experi-
the addition of concomitant surgical procedures ence, the durability of this type of reconstruction
that are performed in more than half of patients.55 is superior to that of cryopreserved homograft
Additional procedures may include resection of or Dacron porcine-valved conduit.60,61 Discigil
RV aneurysm, reconstruction or remodeling of the et al.55 reported the Mayo Clinic experience in 42
RV outflow tract, repair of residual intracardiac patients. Pulmonary valve heterograft prostheses
shunts, intervention for tricuspid or aortic valve were used in 33 patients and homografts in 9. Only
regurgitation, and maze or other antiarrhythmia 5 patients (12%) underwent isolated PV replace-
intervention. It is imperative to determine the ment with concomitant procedures in 37 patients.
coronary anatomy prior to PV replacement from Functional class of patients improved significantly
prior surgical records or angiography images or with 76% being in New York Heart Association
reports. Anomalous proximal coronary artery Class III or IV before the operation, compared
course is not uncommon in TOF patients and has with 97% in Class I or II after operation (P =
an important impact on surgical approach. .0001). The freedom from reoperation in this
Inadvertent transection of an anomalous coro- group was 93 ⫾ 5% and 70 ⫾ 11% at 5 and
nary artery during an operation can cause serious 10 years, respectively. Eight patients underwent
morbidity or even death. successful PV re-replacement without early mor-
Biological valves (porcine and pericardial het- tality at the mean interval of 7.7 years after initial
erografts, homografts) are usually used for PV PV replacement. All patients who underwent
replacement because of the good durability in this repeat PV replacement had a heterograft prosthe-
position and the lack of a need for warfarin anti- sis placed initially. The only significant risk factor
coagulation. However, the use of biological valves for re-replacement by univariate analysis was
carries an inherent risk of the need for reopera- younger age at the time of the initial PV replace-
tion. The cryopreserved pulmonary or aortic ment. In contrast, Lim et al.62 demonstrated that
homograft is an option for orthotropic PV earlier PV replacement prior to symptomatic dete-
replacement. The pulmonary homograft functions rioration showed beneficial effects. Patients in
optimally in the absence of pulmonary hyperten- their series who were still symptomatic following
sion and distal pulmonary artery stenosis. Pulmo- PV replacement (n = 14) were older at the time of
nary homografts have been reported to last longer TOF repair, older at the time PV replacement,
in the pulmonary position than the aortic and had a longer interval between repair of TOF
homografts,59 but they still carry the risk of calci- and PV replacement than asymptomatic patients
fication with resultant stenosis and/or regurgita- (n = 43). Marked symptomatic improvement was
tion and the need for re-replacement. In general, noted in all patients. Therefore, this study as well
both pulmonary and aortic homografts fail by a as others suggested that early PV replacement
combination of regurgitation and stenosis. In our prior to symptomatic manifestation may be
Congenit Heart Dis. 2007;2:386–403
398 Ammash et al.

beneficial.57,62,63 Yemets et al. reported a 10-year mechanical PV replacement are those patients
freedom form reoperation of 86 ⫾ 7% in a group who have had multiple previous operations in the
of 85 patients who had PV replacement at a mean past. When a mechanical PV is used, we aim for a
age of 19 ⫾ 6 years.56 target international nationalization ratio of 3.0 and
To improve the chance of functional recovery, also add aspirin (81 mg).
restoration of the outflow tract at the level of the The use of the valved bovine jugular vein
ventricular arterial junction is important to conduit (Contegra, Medtronic, Inc, Minneapolis,
prevent distortion of the geometry of the pros- MN, USA) is soon to be commercially available
thetic valve, and avoid the risk of early prosthetic and may provide a good alternative to the
valve regurgitation. If this cannot be achieved, it homograft. It is currently available in Europe and
may be prudent to use a stented prosthesis.25 At undergoing clinical trials in the United States.
the present time there is little evidence to support Advantages include greater availability of sizes,
the use of a specific bioprosthetic valve in adults, in ease of handling, and price compared with pulmo-
terms of long-term prosthetic valve function or nary homografts. Brown et al.67 reported early
patient survival. Many factors influence prothesis hemodynamics of the conduit to compare favor-
longevity such as size, and age of the patient at ably with pulmonary homografts with regard to
time of implantation. Whether or not medications obstruction or regurgitation. Long-term results
such as statins or low-dose aspirin influence the are lacking but the conduit may prove to be a good
outcome of valve prosthesis is yet to be deter- alternative to the pulmonary homograft for RV
mined. Preliminary data from our institution outflow tract reconstruction.
suggest that triglyceride levels may impact pulmo-
nary prosthesis longevity.64 Percutaneous Intervention
The use of mechanical valve prosthesis in the Percutaneous balloon dilatation and stent place-
pulmonary position has been limited because of ment for branch pulmonary artery stenosis has
concerns of increased risk of thromboembolic been used for many years and can decrease the
complications. The St. Jude bileaflet mechanical hemodynamic effect of PR. Patients with free PR
valve prosthesis has a low profile, a large effective and branch pulmonary stenosis rarely tolerate PR
orifice area, and excellent hemodynamic profile. well. Such patients should be considered for PV
Unfortunately, 1 study suggested a failure rate of implantation with concomitant relief of pulmo-
35% predominantly from thrombotic complica- nary artery stenosis using pulmonary angioplasty
tions.65 However, these complications occurred performed either percutaneously or at the time of
primarily in patients who were suboptimally anti- the operation with the pulmonary artery exposed.
coagulated. In patients on therapeutic warfarin, Pulmonary artery stent placement at the time of
the complication rate observed was 10%. Stulak operation may be an attractive option in select
et al.66 reported the Mayo Clinic experience of patients.
mechanical PV prostheses in 10 patients. Nine Recent advances in the percutaneous interven-
were anticoagulated with warfarin. During a mean tion, and growing concerns about the risk of
follow-up period of over 8 years, 1 patient multiple reoperations, lead to an interest in percu-
required replacement for outgrowth of her taneous PV replacement using bovine valve of
mechanical prosthesis after 25 years. No case of jugular vein mounted on a stent.68 The first per-
clinically evident mechanical PV prosthesis cutaneous PV implantation was reported by Bon-
thrombosis was noted. One late sudden death hoeffer et al.69 Since that original report, 2 large
occurred 15 years after PV replacement. reports suggest that percutaneous PV implanta-
In our practice, mechanical PV prostheses are tion in the appropriately selected patient is a
considered in patients who need warfarin for relatively safe, effective procedure with durable
another reason such as left-sided mechanical valve short-term results, and should be considered
prosthesis, or in patients with documented accel- as a promising alternative to surgery.65,68,70 Both
erated deterioration of a previously placed PV bio- approaches are safe with an acceptable level of
prosthesis. In addition, there is the occasional morbidity and low mortality. The presence of
patient with atrial fibrillation who will require favorable RV outflow tract morphology is based
long-term warfarin therapy, although this is on echocardiographic and magnetic resonance
increasingly uncommon because of the application imaging evaluation. Favorable features for percu-
of the maze procedure at the time of PV replace- taneous valve replacement include an RV outflow
ment. Other patients who might be considered for tract diameter of less than 24 mm, an RV outflow
Congenit Heart Dis. 2007;2:386–403
Tetralogy of Fallot 399

gradient of greater than 30 mm Hg, the presence QRS duration decreased in the majority, and QRS
of discrete waist or calcification for implantation, duration changes correlated with improvement
and the absence of significant pulsatility. On the in RV end diastolic volume (P value = .001). In
other hand, this procedure should not be consid- another study Doughan et al.74 demonstrated a
ered in patients with limited access to the RV reduction in RV volume and QRS duration in
outflow tract due to occluded central vein or in patients with a preoperative QRS duration of
those with aneurysmal RV outflow tract or in any >155 milliseconds compared with patients with
patient with unfavorable shape, size (>24 mm), and QRS <155 milliseconds who had no decrease in
elastic property of the RV outflow tract. Recent QRS duration. However, it must be emphasized
development of an infundibular reducing device that although these 2 studies clearly demonstrate
may facilitate a percutaneous approach in these that QRS duration can improve after PV replace-
patients with larger outflow tract diameter. Evolv- ment, this may not correlate with reduced risk of
ing device design and experience with this tech- arrhythmias.52
nique will impact the future of re-intervention in Despite the significant improvement noted in
patients with PR following TOF repair. Impor- functional class, QRS duration, RV size, and func-
tantly percutaneous intervention will not address tion after PV replacement, significant residua and
the need for resection of subvalvular hypertrophic sequelae may persist. Conte et al.57 examined the
muscle bundle, pulmonary infundibuloplasty in effect of PVR in 49 patients. The patients who did
patients with severe RV dilatation and large aki- not benefit from PV replacement, in terms of exer-
netic or aneurysmal segment in the RV outflow cise tolerance, had been exposed to PR for a con-
tract, the need for tricuspid valve repair or intra- siderably longer time (18 ⫾ 7 vs. 12 ⫾ 6 years).
operative cryoablation to reduce the incidence of Patients who underwent PV replacement more
atrial and ventricular arrhythmias. than 15 years after TOF repair had only mild
reduction in RV dilatation following surgery.
Therrien et al.75 noted subjective improvement in
Outcome Following PV Replacement
25 adult patients with repaired TOF who under-
Several studies reporting on patients who under- went radionuclide angiography before and after
went PV replacement for PR in TOF have dem- PV replacement. However, exercise duration and
onstrated improvement in the functional class, maximal workload failed to increase significantly.
increased exercise tolerance, reduction in RV end In addition, there was no improvement in RV ejec-
diastolic diameter and volume, and at times, tion fraction and dimension post PV replacement.
improvement in ejection fraction using echocar-
diography or CMR.12,14,25,55,57,62,66,71,72 Bove et al.71
Strategies for Prevention of Late PR During Initial
were the first to demonstrate that RV dysfunc-
TOF Repair
tion associated with PR is reversible and that PV
replacement should be carried out before perma- Every effort is now made to maintain PV compe-
nent RV dysfunction ensues. An increase of tence in order to avoid the recognized problems
more than 5% in RV ejection fraction was noted related to chronic PR in patients following repair
in 7 patients. Warner et al. reported a 30% of TOF. Current operative techniques often
reduction in RV end diastolic diameter using involve a combined transatrial and transpulmo-
echocardiography in 36 patients following PV nary approach involving closure of ventricular
replacement.73 septal defect and relief of the RV outflow tract
Buechel et al.47 reported significant beneficial obstruction. However, a limited RV incision is
remodeling in children with TOF who had CMR often required for patch augmentation of the RV
before and after PV replacement. A significant outflow tract and/or the PV annulus. Under those
reduction in RV dimension, RV mass, and RV end circumstances, the use of a small stiff patch may
diastolic volume was noted after PV replacement. provide a superior hemodynamic state than a large
A recent study demonstrated improved RV and expandable pericardial patch.6 The patch
diastolic function late after PV replacement.12 Pul- should also be positioned to avoid producing
monary valve replacement may also have a benefi- severe PR. The latter could be at the expense of
cial effect on the risk of ventricular arrhythmias. In more residual RV outflow tract obstruction.76
a study by van Huysduynen et al.,72 26 patients Cheung et al.77 reported the result of such pul-
were evaluated preoperatively and 6–12 months monary annulus preservation technique in 118
postoperatively by CMR and electrocardiogram. children undergoing TOF repair in Toronto. This
Congenit Heart Dis. 2007;2:386–403
400 Ammash et al.

approach yielded a lesser need for transannular Accepted in final form: September 18, 2007.
patch (20%), and a higher intraoperative RV
outflow tract gradient (12 vs. 20 mm Hg).
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