Cardiac malpositions and syndromes with right or left atrial isomerism

Cardiac malpositions and syndromes with right or left atrial isomerism

16
Cardiac malpositions and syndromes with right
or left atrial isomerism
Rabih Chaoui
Isomerism and related heart malpositions belong to the
most difficult chapters in pediatric cardiology. According
to the Baltimore–Washington Infant Study,1 which analyzed 4390 congenital heart defects (CHDs) detected in the
first year of life over a period of 10 years (1981–1989),
isomerism was found in 99 cases, accounting for 2.2% of
CHDs. The mortality in this small group was 51% within
the first year of life. In the fetus the true prevalence is,
however, not known, since some forms, especially when
associated with heart block and fetal hydrops, would end
as fetal death, and some other more mild forms of cardiac
malposition or isolated situs inversus may be overlooked
even in a child. The early prenatal detection of an abnormality of this group has a large impact on counseling the
pregnant woman, especially because small details can radically change the prognosis. There are difficulties in achieving a final fetal diagnosis, as the examiner can rely only on
ultrasound, where there are limited possibilities for the
precise differentiation of structures. Furthermore, some
basic knowledge is needed in order to understand some
definitions as well as the classification of defects. In this
chapter, not all aspects of these abnormalities can be covered in detail. It is tried rather to supply the reader with
basic information for a practical approach to suspected
abnormal conditions.
Developmental aspects and
normal body configuration
In contrast to other embryological organs, the thoracic
and abdominal structures develop asymmetrically. There
are well-defined right-sided and left-sided organs and
structures. After completion of lateralization, the ‘normal’
and most common condition found is then called situs
solitus for the visceral arrangement, and levocardia (heart
on the left side) for the thoracic arrangement (Figure 16.1).
In Chapter 12, on fetal cardiac anatomy, the focus was on
the segmental analysis of the upper abdomen and the
heart, showing that under normal conditions in situs solitus the stomach and descending aorta are on the left and
the liver and the inferior vena cava on the right. The
umbilical vein bends to the right, continuing with the
portal sinus. In levocardia the heart apex points to the left
anterior thoracic cavity with normal atrial and ventricular
arrangement (Figure 16.1) and, under normal conditions,
the inferior vena cava is connected to the right atrium and
the pulmonary veins to the left atrium.
Situs inversus, malrotations,
and malpositions of the heart
Compared to the most common condition of situs solitus
and levocardia, there is very rarely a situation where all
organs are rotated exactly to the opposite side, leading to a
mirror-image arrangement. This situation is called situs
inversus. When this mirror-image rotation of abdominal
and intrathoracic organs is complete, the liver and inferior
vena cava are on the left, whereas the stomach and the
descending aorta are on the right (Figures 16.2 and 16.3).
Since the inferior vena cava and the right atrium are concordant, the right atrium and right ventricle are on the left
anteriorly and the left atrium and left ventricle are on the
right posteriorly and the heart axis points to the right anterior thorax, a situation called dextrocardia (Figure 16.4)
(mirror-image dextrocardia or situs inversus with dextrocardia, or situs inversus completus). In these conditions
associated heart defects are rare. The true incidence of this
situation is low, but also not exactly known, since persons
with this abnormality are asymptomatic and are not identified until an X-ray, ultrasound, or medical intervention
is performed. Because this condition is extremely rare, it
can be recommended that, before making this diagnosis,
the examiner checks the fetal position and the transducer
orientation. According to our experience, we have found
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Fetal Cardiology
Figure 16.1
The two important planes in assessing isomerism and other cardiac malpositions. The normal sonoanatomy of the upper abdomen
with situs solitus (left) and the heart in levocardia (right). R, right; L, left; ST, stomach; VCI, inferior vena cava; AO, aorta; RV, right
ventricle; LV, left ventricle.
Figure 16.2
Situs inversus. The fetus is in vertex position and in the upper
abdomen a mirror-image rotation is found with the stomach
(St.) and the aorta (Ao) on the right side and the inferior vena
cava (Vci) and liver on the left side.
Figure 16.3
The heart in a fetus with complete situs inversus and mirrorimage dextrocardia. The fetus is in vertex position. The heart
points to the right anterior thorax (arrow). The right ventricle
(RV) (with trabeculation) is on the left side and in the anterior
thorax. The descending aorta (Ao) is on the right side. LA, left
atrium; RA, right atrium.
Cardiac malpositions and isomerism
241
Figure 16.4
Two examples of dextropositions: on the left, a fetus with left-sided congenital diaphragmatic hernia (ST, stomach) with a shifting
of the heart into the right thorax; on the right, a fetus with the rare finding of right pulmonary agenesis. The heart fills the space
of the right lung and the left lung fills the thorax.
that a high risk for situs inversus was in a family with a
previous child with this condition, in consanguineous
couples, and in the offspring of diabetic mothers. However, there are other conditions where the mirror-image
arrangement is partial: either only affecting the heart, as in
dextrocardia (with situs solitus); or affecting the visceral
organs, as in situs inversus with levocardia.2 In these
conditions heart defects are more common.
The heart position and axis are important features to
check while analyzing the heart. Compared to its normal
position in the left chest with a normal base–apex axis of
45° to the left side, cardiac malpositions are divided into
dextrocardia, levocardia, mesocardia, and ectopia cordis.
As already stated, dextrocardia is present when the heart
is in the right hemithorax with the axis pointing to the
right. Mesocardia is found when the heart points to the
midline of the thorax. Many children having mesocardia
are incorrectly grouped in the dextrocardia group, since
on X-ray the heart seems more on the right side. Levocardia (heart on the left, i.e. the normal position) is mainly
considered when there is a situs inversus or ambiguus, to
stress that the heart still points to the left side.
Cardiac dextroposition (displacement to the right) is
found when the heart is shifted into the right chest with
the axis still pointing to the left, as observed in left-sided
congenital diaphragmatic hernia, left-sided intrathoracic
masses, or fluid accumulation, in agenesis of the right lung
(Figure 16.5), or in scimitar syndrome.
Similarly, levoposition (displacement to the left) is
seen when the heart is shifted into the left thoracic cavity
with the axis still pointing to the left, as typically found
in right-sided diaphragmatic hernia or some other
right-sided thoracic lesions.
Right and left atrial isomerisms
in the fetus
Conversely to the above-cited very rare abnormalities with
a mirror-image arrangement of the visceral and intrathoracic organs, there are more common conditions with an
incomplete lateralization (heterotaxy) of these organs
during embryological rotation, showing an indeterminate
visceral situs. In these conditions, the arrangement is called
situs ambiguus (indeterminate or uncertain situs) and is
the most complex form of visceral and atrial arrangement.
This group of defects has many synonyms, such as heterotaxy syndromes, cardiosplenic syndromes, or asplenia–
polysplenia syndromes or isomerisms, and the conditions
are regularly associated with complex cardiac defects.
In these abnormal lateralizations of the visceral
and intrathoracic structures, there is a tendency to
symmetric development of the normally asymmetric
organs, associated with either a bilateral right-sidedness
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Fetal Cardiology
Figure 16.5
Fetus with left isomerism showing, in the upper abdomen, situs ambiguus with the stomach (ST) on the right side (R) and an
interruption of the inferior vena cava with azygos (AZ) vein persistence. The double-vessel sign is typical of left isomerism. In the
four-chamber view the heart shows an atrioventricular septal defect (green arrows) and behind the heart again the double-vessel
aorta (Ao) and azygos (compare with Figure 16.13). These cases of atrioventricular septal defects are not associated with Down
syndrome.
Figure 16.6
This fetus was referred with bradycardia. M-mode shows the presence of a complete heart block: the atria (A) have a normal sinus
rhythm (yellow arrows) whereas the ventricles show bradycardia (50 beats per minute) (red arrows). Examination of the fourchamber view reveals the diagnosis: a dilated heart with pericardial effusion, and behind the heart side-by-side with the
descending aorta there is a second vessel, which is the dilated azygos vein; this is a typical finding in left isomerism.
Cardiac malpositions and isomerism
243
Figure 16.7
Two examples of left isomerism with the ‘double vessel sign’ (dilated azygos and aorta side-by-side) with the stomach on the left
(left case) and on the right (right case). This example shows that the diagnosis is achieved by evaluation of the vessels’ position
rather than the position of the stomach (compare also Figure 16.3).
Figure 16.8
Left isomerism with atrioventricular (AV) septal defect with
azygos continuation side-by-side with the aorta.
(right isomerism) or bilateral left-sidedness (left isomerism). Ivemark3 noted the association of spleen anomalies
with some cardiac defects. Because the spleen develops as
a left-sided organ it was in the past a sign for classification,
asplenia being the previous name of right isomerism and
polysplenia of left isomerism. This group of developmental defects were therefore called cardiosplenic syndromes.
However, it was found that spleen presence, position, and
number do not have definitive diagnostic value, and this
terminology was abandoned4 (although it is often still used
in clinical pediatric cardiology).
Knowing that the heart develops according to welldefined cardiac segments, Van Praagh5 proposed a classification according to the anatomy and connections of these
segments, known as the segmental approach. The constant
starting point for classifying these conditions is the anatomy of the atria. Therefore, diseases with isomerism are
now divided into right atrial and left atrial isomerism.
The identification of these anomalies and their differentiation may be easier for the pathologist during necropsy.
In the fetus the diagnostic possibilities are reduced, and
the reliable diagnosis or differentiation between right or
left isomerism can be very difficult to achieve prenatally.6
Even for the experienced examiner this group of anomalies is considered a challenge. The diagnostic approach
using ultrasound is based on the approach proposed by
Huhta et al7 for neonatal echocardiography, focusing on
the upper abdomen and the relationship between the
venous system and the atria. The central point of diagnosis
is the anatomy of the atria defined by their shape and their
appendages. The left atrial appendage is finger-like and
has a narrow base, whereas the right atrial appendage is
pyramidal in shape and its base is rather broad. The
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Fetal Cardiology
Figure 16.9
Thoracic cross-section (left) and
longitudinal view of aorta descendens
and dilated azygos vein.
Figure 16.10
Left isomerism. If persistence of an azygos vein is suspected, the examiner can confirm the diagnosis by using color Doppler.
In a frontal view the descending aorta and the azygos vein can be seen side-by-side with different flow directions (left). In its
further course the azygos vein crosses the diaphragm and connects with the superior vena cava to enter the right atrium (middle).
Doppler findings demonstrate the venous pattern (right) (arrhythmia with the associated heart block).
appendages can be visualized in a plane slightly cranial to
the four-chamber view, but are not identified reliably
under many conditions. In a recent retrospective study8
on 30 fetuses with isomerism it was, however, shown
that prenatally the morphology of the atrial appendages
could have been suspicious in 19 cases, with the typical
bilateral sickle-shape appearance in left and the bluntshape appearance in right isomerism.
Since the connecting veins are part of the atrial anatomy,
the venoatrial connection is the leading diagnostic sign for
Cardiac malpositions and isomerism
diagnosis. However, there are no heart defects that are
pathognomonic for the one or the other diagnostic group.
In the following sections some features associated
with each anomaly are enumerated, which might help in
making diagnoses.
245
The types of cardiac malformation associated with left
and right isomerism are complex, showing a considerable
overlap. Except the azygos continuation of the inferior
vena cava, considered as a typical sign of left isomerism,
Left atrial isomerism
In this condition of double left-sidedness, right-sided
structures such as the inferior vena cava and the right
atrium with sinus node are absent or may have developed
abnormally. Therefore, two leading signs in left isomerism
can be expected: first, the ‘interruption’ of the inferior
vena cava in its intrahepatic part and its persistence as the
azygos (or hemiazygos) vein (Figures 16.6–16.10); second,
arrhythmia with heart block (malformed sinus node)
(Figures 16.10 and 16.11). The azygos continuation of
the interrupted inferior vena cava has been shown to be
present in most cases with left isomerism (> 80%). It can
be recognized by the observation of the aorta and the
(dilated) azygos vein on its right or left side (hemiazygos)
either in the upper abdomen (Figure 16.7) or at the level
of the four-chamber view (Figure 16.8).9. Sheley et al10
described it as the ‘double-vessel sign’, and found it in
all eight fetuses with left isomerism that they examined,
but also in one false-positive case with right isomerism. In
another more recent study in 22 fetuses with left
isomerism,11 21 showed this azygos continuation sign. If
the examiner is aware of this sign, he can easily detect
it prenatally on real-time imaging and confirm it using
color Doppler (Figures 16.9 and 16.10). The azygos vein
is then visualized leading into the superior vena cava
or into a persisting left superior vena cava (Figures 16.10
and 16.12).
Figure 16.11
Transverse view across the upper thorax showing the so-called
three-vessel view (VCS, superior vena cava; AO, aorta; TP,
pulmonary trunk). In this fetus with left isomerism the (dilated)
azygos vein is seen to connect to the superior vena cava.
Furthermore, to the left of the pulmonary trunk, there is a
fourth vessel, which is the left persistent superior vena cava
(LVCS).
Figure 16.12
This fetus was referred at 14 weeks
because of nuchal edema (and
beginning hydrops) associated with
bradycardia. We found a heart block,
a stomach (St) on the right side (left)
and levocardia (H) with a heart
defect. The heart showed a
univentricular atrioventricular
connection with a small (v) and a
dilated ventricle (V) connected by a
ventricular septal defect (*). The liver
lay centrally. After termination of
pregnancy because of suspected
left isomerism, the diagnosis
was confirmed at autopsy
(see Figure 16.14).
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Fetal Cardiology
Figure 16.13
Necropsy of the 14-week fetus shown
in Figure 16.13, demonstrating the
central liver (left), the heart with two
left atrial appendages (arrows), and,
after removing the liver, the stomach
(St) on the right side.
Figure 16.14
Right atrial isomerism. In the upper abdomen the aorta (AO) and inferior vena cava (VCI) are on the same side (here the right side
(R)) and the inferior vena cava is anterior to the aorta (arrows). The stomach (ST) is nearer the midline than on the left. In a
longitudinal plane (right) both the aorta (blue) and the inferior vena cava (red) are seen in one plane and are both directly anterior
to the spine, a simultaneous visualization not seen under normal conditions.
there are no cardiac defects permitting a strict classification into one or other group of isomerism. The conditions
of a heart with left atrial isomerism seem to be less severe
than those with right isomerism, demonstrating a normal
ventriculoarterial junction in almost 70% of cases.12 These
hearts tend to be biventricular, and on many occasions a
ventricular septal defect or an atrioventricular septal defect
is present.4,13 The association of an atrioventricular septal
defect with complete heart block is considered to be
pathognomonic for left atrial isomerism6 and should
prompt careful examination of the venous connections.
Heart block detected in the early second trimester is also
Cardiac malpositions and isomerism
247
very likely to be due to left isomerism and not to maternal
autoantibodies14 (Figures 16.13 and 16.14). In the study
reported above in 22 fetuses with left isomerism, a persisting bradycardia was found in 12/22 cases.11 The position of
the heart can be on the left, on the right, or in the midline.
The most severe complex extracardiac malformation
observed in left isomerism is extrahepatic biliary atresia
with absence of the gallbladder.
Right atrial isomerism
Figure 16.15
In this fetus with right isomerism the stomach was also found
to be central. In late pregnancy we observed a herniation of
the stomach into the thoracic cavity (arrows) through the intact
diaphragm.
In this condition of double right-sidedness, left-sided
structures such as the left atrium, the pulmonary veins,
and the upper gastrointestinal tract are likely to be found
malformed. In this group of complex malformations there
are no characteristic features, such as interruption of the
inferior vena cava or the heart block described for left
isomerism.
The inferior vena cava is present and is generally on the
same side as the descending aorta (Figures 16.15–16.17).
The visceral heterotaxy is more common and severe in
right isomerism, and anomalies of the upper abdomen are
more likely to be found in right than in left isomerism;
these include not only the common absence of the spleen,
but also the symmetrical liver, and non-fixation of the gastrointestinal tract leading to various degrees of malrotation (Figures 16.15 and 16.16). Atresia of the esophagus or
Figure 16.16
Right isomerism with the typical sign of the juxtaposition of inferior vena cava (VCI) and aorta as in Figure 16.15 either on the left
(left case) or on the right side of the spine (right case). The position of the stomach can be on the right or on the left side (the
stomach is generally more central and the liver is more enlarged).
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Fetal Cardiology
duodenum can be found as well as the herniation of a
midline-positioned stomach (Figure 16.18). Heart defects
in right isomerism are likely to be more severe than those
with left isomerism. Among the cardiac defects, total
anomalous pulmonary venous drainage is found in 70% of
cases (rarely in left isomerism) (Figure 16.19). Hearts with
right atrial isomerism can also show an atrioventricular
septal defect, but are more likely to be associated with a
univentricular atrioventricular connection and exhibit a
much higher incidence of abnormal ventriculoarterial
connections (double outlet ventricle, malposition of the
great arteries). These hearts show a much higher frequency
of pulmonary stenosis or atresia (Figure 16.20). An absence
of the coronary sinus is found in 85% of cases. A left
persisting superior vena cava is found very frequently
(Figure 16.12). In a recent study of 21 fetuses with right
isomerism,15 20 had complex cardiac anomalies, predominantly atrioventriculary septal defects and right ventricular obstruction in 62% and 48%, respectively Only 12
fetuses in this study showed a juxtaposition of aorta and
inferior vena cava, and out of six cases with anomalous
pulmonary venous return four were not diagnosed prenatally. Therefore, when right isomerism is suspected in a
fetus, the connections of the pulmonary veins should be
examined carefully to rule out the critical infradiaphragmatic pulmonary venous return.16
Prognosis in isomerism
Figure 16.17
Right isomerism in a 13-week fetus discerned by the detection
of a cardiac anomaly at routine scan. The stomach was found
to be on the right side, which prompted targeted examination
of the vessels showing the typical sign of the juxtaposition of
VCI and aorta.
It is known that left and right isomerisms are associated
with a poor prognosis.4,13 Individual differences, depending on the specific finding, should be considered when
counseling parents after a prenatal diagnosis, but it is often
difficult to assess the prognosis from the prenatal scan in
these conditions. Fetuses with left isomerism show a poor
prognosis in utero when associated with complete heart
block and hydrops. Cardiac failure and hydrops may occur
very early, leading to spontaneous in utero demise. Postnatally, the prognosis may be further complicated by the
underlying heart defect, although this is generally less
severe than in right isomerism. Among extracardiac
anomalies, biliary atresia can be considered as the most
severe finding, which cannot be definitively ruled out in
Figure 16.18
Fetus with right isomerism. Owing to
the inferior vena cava connection the
atrium on the left is recognized as a
right atrium and the atrium on the
right receives the (abnormal)
connections of the pulmonary veins.
There is a univentricular
atrioventricular connection to one
ventricle (V). The outflow tract
evaluation revealed pulmonary atresia:
color Doppler demonstrates a normal
antegrade flow through the aorta (AO)
and retrograde flow across the ductus
arteriosus (DA) into the pulmonary
trunk (TP). Univentricular hearts and
right-sided obstructions are more
represented in right isomerism
(see text).
Cardiac malpositions and isomerism
Figure 16.19
Abnormal pulmonary venous drainage in a fetus with right
isomerism.
249
utero. Under some conditions, children with left isomerism show a better survival rate than those with right
isomerism.
The diagnosis of right atrial isomerism is very difficult
in utero and should be considered in every fetus with a
complex cardiac malformation, especially when cardiac or
situs malposition are suspected. The severity of the disease
usually appears postnatally, and is due to the abnormal
pulmonary venous connection, to the ductus-dependent
pulmonary perfusion in right outflow tract obstruction, or
to the complex chamber anatomy. Within the first year of
life, 79–94% of all children with right isomerism were
reported to die, with or without operation.13 A long-term
risk in patients with right isomerism is also infection due
to asplenia, which is often associated.
The association with chromosomal aberrations such as
trisomy 21, 13, 18, or others is extremely rare, since the
diagnosis of isomerism rather rules out such chromosomal
aberrations. Yates et al17 reported, however, a fetus with
Figure 16.20
Summary of the four typical findings in the upper abdomen in situs solitus (top left), situs inversus (top right), right isomerism
(bottom left), and left isomerism (bottom right). The inferior vena cava (blue) and its position relative to the aorta (red) are main
landmarks.
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Fetal Cardiology
isomerism associated with a 22q11 deletion. Recent results
in families with recurrences of visceral heterotaxy cases
showed that the gene for these malformations is probably
localized on the long arm of the X chromosome (region
between Xq24 and X27.1 but probably on Xq26).18 In the
near future, the prenatal diagnosis of these abnormalities
may be revolutionized by this new knowledge.
Conclusion
Every fetal heart defect should be analyzed in a segmental
approach in order to detect (or rule out) an isomerism.
This approach can be difficult to achieve in some cases and
even omitted in others. Therefore, the examiner should
always rule out isomerism when the following ultrasound
signs are found: cardiac or stomach malpositions, a complex cardiac defect, fetal heart block, abnormal venous
connections, and dilatation of the azygos vein.
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