Tetralogy of Fallot
Tetralogy of Fallot (ToF) is one of the most common cyanotic heart
defects with an incidence of 3-5 per 10,000 live births, accounting for
approximately 7-10 % of congenital heart defects in liveborn
children81. Historically, the underlying anatomic
condition was attributed to Etienne-Louis Fallot in 1888, who introduced
the term ‘La Maladie Bleue’, the Blue Disease82,83.
However, it was the merit of the Danish anatomist Niels Stenson, who
described this pathology during a necropsy of a malformed fetus with
ectopia cordis already in 167184. In 1924, Maude
Abbott coined the term ‘Tetralogy of Fallot’, as Fallot was the first to
link the defining classical clinical features: RV outflow tract
obstruction (RVOTO), ventricular septal defect, overriding aorta, and
right ventricular hypertrophy.
Embryologically, anterocephalad deviation of the developing outlet
ventricular septum together with hypertrophy of septoparietal
trabeculations determine both the RV outflow tract obstruction and the
malaligned ventricular septal defect with an overriding
aorta81. The exact cause of this combination of
lesions remains unknown, and its etiology is thought to be
multifactorial including both environmental and genetic factors. The
reported incidence of chromosomal anomalies in ToF is 29 % (including
microdeletion of 22q11.2). According to a recent systematic review,
22q11.2 microdeletion is apparently three times more common in ToF with
PA. Notably, aneuploidies are more often in classical
ToF85. Other concomitant cardiac anomalies comprise an
atrioventricular septal defect (AVSD), a right-sided aortic arch (RAA),
an anomalous origin of the coronary arteries, a left persistent superior
vena cava and total anomalous pulmonary venous return (TAPVR). In subset
of cases, ToF is complicated by a severely underdeveloped or even absent
pulmonary valve that is replaced by a thickened infundibulum and
rudimentary valve tissue at the level of the pulmonary valve annulus,
with usually massively dilatated pulmonary arteries, as stated below.
In clinical practice, there is a broad spectrum of this condition. The
most common variety of ToF consists of a mild-to-moderate RVOTO and
normally sized branch pulmonary arteries. In utero , RV
hypertrophy is almost always absent as the pressure gradient between of
right and left ventricles is rather low, and the four-chamber cardiac
view appears to be normal. On the other hand, there may also be complete
obstruction of the RVOT, which is similar to pulmonary atresia with VSD.
The pulmonary blood flow in this case is maintained from the aorta
either retrogradely via the ductus arteriosus supplying the PAs or via
major aortopulmonary collateral arteries (MAPCAs). In figure 7, the
cardiac anatomic changes in a fetus with ToF/PS are illustrated.
Notably, the 3VT and 4CV views are normal including the cardiac axis,
and the DA is patent, as in 80-90 % of all ToF cases. A perimembraneous
VSD is clearly seen in the 5CV and LVOT views with an overriding aorta.
The main pulmonary artery is slightly smaller (than the ascending aorta)
in the RVOT and ductal arch views. Additional color Doppler
interrogation revealed laminar, nonturbulent flow across the PV,
precluding a hemodynamically significant RVOTO. Yeo and Romero published
a report of a case of ToF/PA analyzed with the FINE method and clearly
demonstrated a narrow and atretic RVOT86. It has
previously been shown that an abnormal cardiac axis in fetuses with ToF
is highly predictive of the presence of pulmonary atresia and a
right-sided aortic arch and is linked to postnatal
death87. In this regard, a recent study on the
prevalence of genetic abnormalities supported the impact of cardiac
angle assessment as levorotation of the cardiac axis was noticed in
two-third of ToF cases with genetic anomalies (assessed by chromosomal
microarray analysis)88. Lv et al. published on a big
data analysis for the differential diagnoses of ToF; based on their
results, the PA/Ao ratio constitutes the primary parameter to
distinguish ToF from large malalignment VSD, which is in line with
observations by Wu and colleagues, who calculated 11 different
cardiovascular dimensions applied on STIC volumes and were able to show
that all fetuses with ToF had abnormal Ao z-scores and reduced PA/Ao
ratios89,90. A recent multicenter study confirmed
these parameters to be the most valid predictors of neonatal
intervention (PV:AoV ratio <0.6, PV:AoV z-score difference
≥5)91.