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\begin{document}

\title{Surgical Management of Hearts with Isomeric Atrial Appendages}



\author[1]{Ujjwal Chowdhury}%
\author[2]{Robert Anderson}%
\author[3]{Diane E. Spicer}%
\author[4]{Lakshmi  Sankhyan}%
\author[1]{Niraj Pandey}%
\author[1]{Shikha Goja}%
\author[1]{Palleti Rajashekar}%
\author[1]{Balaji Arvind}%
\author[1]{Doniparthi Pradeep}%
\affil[1]{All India Institute of Medical Sciences Cardio-Thoracic Sciences Centre}%
\affil[2]{Newcastle University}%
\affil[3]{Johns Hopkins All Children's Hospital Heart Institute}%
\affil[4]{Department of Cardiothoracic Surgery All India Institute of Medical Sciences Bilaspur Himachal Pradesh}%


\vspace{-1em}



  
  \date{May 16, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Background and aim:} On the basis of previously published
accounts, coupled with our own experience, we have assessed the surgical
approaches to patients with isomeric atrial appendages.
\textbf{Methods}: We reviewed pertinent published studies on surgical
treatment of individuals with isomeric atrial appendages, with the
pertinent surgical details provided by most of the manuscripts.
\textbf{Results}: Half of patients with right isomerism, and two-thirds
of those with left isomerism have bilateral superior caval veins. Azygos
extension of the inferior caval vein is reported in three-quarters of
those with left isomerism. The coronary sinus is universally absent in
right isomerism, along with totally anomalous pulmonary venous
connection, and is absent in two-fifths of those with left isomerism..
Univentricular atrioventricular connections are expected in up to
three-quarters of those with right isomerism. Atrioventricular septal
defect is reported in up to four-fifths, more frequently in right
isomerism, with such patients typically having discordant
ventriculoatrial connections or double outlet right ventricle. Reported
mortalities extend to 85\% for those with right, and 50\% for those with
left isomerism. In right isomerism, mortality is up to 54\% for
systemic-to-pulmonary arterial shunting, up to 75\% for univentricular
repair, and up to 95\% for repair of totally anomalous pulmonary venous
connection itself. No more than one-quarter had undergone Fontan
completion, with reported mortalities of 21\%. \textbf{Conclusion}:
Early surgical results are satisfactory in patients with left isomerism,
but disappointing for those with right. Recent advances in cardiac and
liver transplantation may offer improved survival.%
\end{abstract}%



\sloppy


\textbf{Surgical Management of Hearts with}

\textbf{Isomeric Atrial Appendages}

\textbf{Running title: Isomeric Atrial Appendages}

\textbf{Ujjwal Kumar Chowdhury, MCh, Diplomate NB\textsuperscript{1}}

\textbf{Robert H. Anderson, BSc, MD, PhD (Hon), FRCPath, FRCS Ed
(Hon)\textsuperscript{2}}

\textbf{Diane E. Spicer, BSc\textsuperscript{3}}

\textbf{Lakshmi Kumari Sankhyan, MCh\textsuperscript{4}}

\textbf{Niraj Nirmal Pandey, DM\textsuperscript{1}}

\textbf{Shikha Goja, MS\textsuperscript{1}}

\textbf{Palleti Rajasekar, MCh\textsuperscript{1}}

\textbf{Balaji Arvind, DM\textsuperscript{1}}

\textbf{Doniparthi Pradeep, MCh\textsuperscript{1}}

Cardiothoracic Centre, All India Institute of Medical Sciences, New
Delhi\textsuperscript{1} and Bilaspur, Himachal
Pradesh\textsuperscript{4}

Institute of Biomedical Sciences\textsuperscript{2}, Newcastle
University, Newcastle-upon-Tyne, United Kingdom

\textsuperscript{3}Heart Institute, Johns Hopkins All Children's
Hospital, St. Petersburg, Florida, USA and Department of Pediatric
Cardiology, University of Florida, Gainesville, Florida, USA

\emph{Correspondence:}

\textbf{Dr. Ujjwal Kumar Chowdhury, M.Ch., Diplomate NB}

Professor

Department of Cardiothoracic and Vascular Surgery

AIIMS, New Delhi-110029, INDIA

Tel.: 91-11-26594835

Fax: 91-11-26588641

Email: ujjwalchowdhury@gmail.com

Orcid ID: http: //orcid.org/0000-0002-1672-1502

\textbf{Word Count:} Abstract (243), Text (4256), References (1777),
Figure Legends (890)

\textbf{Statement of human rights/ethical approval:} The authors assert
that all procedures contributing to this study comply with the ethical
standards of the relevant national guidelines on human experimentation
and with the Helsinki declaration of 1975, as revised in 2008.

\textbf{Conflict of interest} : Nil

\textbf{Source of funding} : Nil

\textbf{Availability of Data:} Data available in the cited materials



\textbf{Abstract}

\textbf{Background and aim:} On the basis of previously published
accounts, coupled with our own experience, we have assessed the surgical
approaches to patients with isomeric atrial appendages.

\textbf{Methods} : We reviewed pertinent published studies on surgical
treatment of individuals with isomeric atrial appendages, with the
pertinent surgical details provided by most of the manuscripts.

\textbf{Results} : Half of patients with right isomerism, and two-thirds
of those with left isomerism have bilateral superior caval veins. Azygos
extension of the inferior caval vein is reported in three-quarters of
those with left isomerism. The coronary sinus is universally absent in
right isomerism, along with totally anomalous pulmonary venous
connection, and is absent in two-fifths of those with left isomerism..
Univentricular atrioventricular connections are expected in up to
three-quarters of those with right isomerism. Atrioventricular septal
defect is reported in up to four-fifths, more frequently in right
isomerism, with such patients typically having discordant
ventriculoatrial connections or double outlet right ventricle. Reported
mortalities extend to 85\% for those with right, and 50\% for those with
left isomerism. In right isomerism, mortality is up to 54\% for
systemic-to-pulmonary arterial shunting, up to 75\% for univentricular
repair, and up to 95\% for repair of totally anomalous pulmonary venous
connection itself. No more than one-quarter had undergone Fontan
completion, with reported mortalities of 21\%.

\textbf{Conclusion} : Early surgical results are satisfactory in
patients with left isomerism, but disappointing for those with right.
Recent advances in cardiac and liver transplantation may offer improved
survival.

\textbf{Key words:} Asplenia, Functionally univentricular heart,
Hepatopulmonary and portopulmonary syndrome, Isomerism of atrial
appendages, Left isomerism, Obstructed anomalous pulmonary venous
connection, Polysplenia, Right isomerism, Visceral heterotaxy



\textbf{Introduction}

Described initially as ``Ivemark syndrome'', there is still no agreement
as how best to segregate individuals with jumbled-up thoracic and
abdominal organs.\textsuperscript{1-4} Usually considered under the
overarching term ``heterotaxy'', \textsuperscript{2-7} two specific
subsets exist within the overall group.\textsuperscript{2-7} The
existence of an isomeric arrangement of the lungs and bronchial tree was
long since established as a discriminating feature, but arguments have
raged as to whether isomerism might exist within the
heart.\textsuperscript{5-15} It has now been shown that, when assessed
on the basis of the extent of the pectinate muscles relative within the
atrial appendages relative to the atrial vestibules, cardiac isomerism
is a real entity.\textsuperscript{13} The two subsets thus identified
encompass a wide range of anatomical variants, characterized by complex
systemic and pulmonary venous connections, and complicated intracardiac
anatomy. The strategies for treating these patients remain equally
complicated. To date, most publications assessing the significance of
the isomeric arrangements have been based on necropsy studies, case
reports, or small case series.\textsuperscript{8-13} Only limited large
scale clinical studies have emphasized the potential significance of the
isomeric features.\textsuperscript{14-22} With all of this in mind, we
have assessed the published clinical and necropsy data to determine the
influences of right as opposed left isomerism on the surgical outcomes,
including re-interventions.

\textbf{Methods}

We identified publications than might relate to the presence of
isomerism in the setting of so-called ``visceral heterotaxy''. From
these publications, we collated and analyzed the anatomical descriptions
of the systemic and pulmonary venous connections, and the presence of
associated cardiac and non-cardiac anomalies, paying special attention
to surgical and non-surgical treatments used and their outcomes. The
search engines employed were PubMed, Google Scholar, Cochrane Database
for Systematic Reviews, Cochrane Central Register of Controlled Trials,
Ovid Medline, ACP Journal Club, Ovid EMBASE, and Database of Abstracts
of Review of Effectiveness in all languages. We made an individualized
review of 62 investigations,\textsuperscript{1-23,26-64} incorporating
these findings with the results of US Scientific Registry of Transplant
Recipients Data, along with results emanating from Loma Linda
University.\textsuperscript{24,25} Due to limited sample sizes, the
heterogeneity of clinical state at the time of surgical intervention,
inclusion of necropsy data, and the difficulties in selection of
appropriate cardiac quantifiable end points, it did not prove possible
to perform a meta-analysis.

\textbf{Incidence}

On the basis of the New England Regional Infant Cardiac Program, those
with isomeric atrial appendages can be inferred to account for just
under one-twentieth of all infants with congenital cardiac
malformations.\textsuperscript{26} The reported incidence in necropsy
studies is around 3\%, but no more than 1.5\% in echocardiographic
investigations.\textsuperscript{7,9-13,27} Isomerism is said to occur in
approximately one out of every 5000-7000 live births with patients of
Asian descent.\textsuperscript{9-13,27} Right isomerism is more
frequently reported in necropsy studies compared to surgical series,
reflecting the complexity of the cardiac anomalies, poor natural
outcome, inoperability, and increased risk of
sepsis.\textsuperscript{7,9-13,27}

\textbf{Results}

\textbf{Demographics}

The age of patients with right isomerism at initial diagnosis, as
assessed from the literature, ranges from birth to 22.3 years, with a
median of 7.7 months. Among survivors, approximately nine-tenths
presented in the neonatal period, having been recognized at birth in
almost two-thirds. Half of these patients required prostaglandin
infusion at presentation to maintain oxygen
saturation.\textsuperscript{14-19,22} For those with left isomerism, age
at initial diagnosis ranged from birth to 35 years, with a median of 2
days. Of these two-thirds were females, whereas only half of those with
right isomerism were female. Up to one-sixth of reported patients with
left isomerism have extracardiac lesions but normal hearts. We have
excluded these individuals from further study. It remains the case,
nonetheless, that approximately one-fifth of reported patients with left
isomerism died shortly after birth, with about half not having surgery
and dying during infancy.\textsuperscript{16,17,20}

\textbf{Diagnosis}

Even now, it remains difficult to distinguish between the subsets on the
basis of clinical identification of the atrial
appendages.\textsuperscript{27-32} Almost all children with right
isomerism are in sinus rhythm. Abnormal p wave morphology and slow
atrial rhythm are associated with left isomerism, with complete heart
block occurring in about 10\%.\textsuperscript{30} Howell-Jolly bodies,
a prominent feature in right isomerism, are found on peripheral blood
smears.\textsuperscript{29,30} The status of spleen can be confirmed by
abdominal ultrasound or a radionuclide spleen
scan.\textsuperscript{2,3,6-13,15} Since intestinal malrotation is a
frequently associated lesion, a barium study is frequently advocated,
especially for those with right
isomerism.\textsuperscript{16,30}Tracheobronchial anatomy, best revealed
using a high voltage aortopulmonary view.\textsuperscript{6,11,12,30}
can be used to distinguish right versus left
isomerism.\textsuperscript{12,23,31}.\textsuperscript{30-32} It is
bronchial arrangement that correlates best with the arrangement of the
atrial appendages.\textsuperscript{31-33} This is significant, since it
still remains a problem specifically to diagnose specifically the
features of the atrial appendages.\textsuperscript{4,31} When seeking to
make the diagnosis by inference, echocardiography assessment of the
abdominal great vessels and hepatic venous drainage is more accurate
than assessment of the abdominal organs.\textsuperscript{27,29} Although
prenatal diagnosis can be made by echocardiography, this had no impact
on survival.\textsuperscript{32} Transesophageal echocardiography is
becoming helpful in confirming the diagnosis (Figure 1). It is computed
tomography, and/or three-dimensional cardiac magnetic resonance,
nonetheless, that now provides the best comprehensive
assessment.\textsuperscript{34,35}

\textbf{Surgical Anatomy}

\textbf{The intracardiac anatomy of right isomerism}

Both atrial appendages have similar external and internal
configurations. \textsuperscript{2,3,7,12,13,30} They have a broad
junction, separated by an extensive terminal groove, with the venoatrial
components. Presence of pectinate muscles extending to the crux of the
heart on both sides is the essential diagnostic feature. Because of the
presence of bilateral morphologically right appendages, the pulmonary
venous connections will always be anatomically anomalous, even when the
veins connect to one or other of the atrial chambers (Figure 2). The
connection is usually through a midline confluence that connects to the
atrial roof (Figures 3 and 4). The channel often becomes stenotic. The
superior caval veins, frequently bilateral, connect directly with the
atrial roofs. The coronary sinus is universally absent. Hence, the
coronary veins drain directly into the atrial cavities, usually at the
level of the vestibules, but on occasion at a distance from the
atrioventricular junction.\textsuperscript{36} It is most unusual to
find interruption of the inferior caval vein when there is right
isomerism. In some instances, all of the pulmonary veins can drain to
either the right-sided or the left-sided atrial chamber, while all the
systemic veins connect to the other atrial chamber. Such quasi-usual or
quasi-mirror-imaged venous drainages do not detract from the fact that
the atrial arrangement remains that of right isomerism.

The atrial chambers typically connect to the ventricles through a common
atrioventricular junction, and often the atrial septum is no more than a
myocardial strand. Although found most frequently with double inlet
right ventricle, each of the atrial chambers can be connected to its own
ventricles across the common junction. Half of the heart will then be
concordantly connected, while the other half will be discordantly
connected. The biventricular atrioventricular connection, therefore, is
mixed. It is frequent in this setting to have duplicated
atrioventricular nodes, producing the so-called Monckeberg
sling.\textsuperscript{37} It is very unusual to find concordant
ventriculo-arterial connections. Most usually the connections are double
outlet right ventricle or transposition. Obstruction or atresia of the
outflow tract of the morphologically right ventricle is expected. It is
very rare to find a common arterial trunk, or tetralogy of Fallot. When
pulmonary atresia is present, then the pulmonary arteries are usually
fed through an arterial duct, which can be right or left-sided (Figure
5). The aortic arch, along with the cardiac apex, can be right-sided or
left-sided.

\textbf{The Intracardiac Anatomy of Left Isomerism}

It is again the extent of the pectinate muscles relative to the
atrioventricular junctions that serves as the distinguishing feature of
the morphologically left appendage. In left isomerism, there is always a
smooth vestibule between the margin of the appendage and the cardiac
crux. Since both atriums will have a morphologically left appendage, the
pulmonary venous connections are morphologically normal, albeit that
symmetrical drainage, with two pulmonary veins connecting to an atrium
on each side, is frequent. When all the pulmonary veins are connected to
one of other of the atrial cavities, it is frequent to find quasi-usual
or quasi-mirror-imaged venous drainage. It is the rule to find anomalies
in the systemic venoatrial connections, most usually interruption of the
inferior caval vein, with continuation through the azygos venous system
(Figures 6 and 7). The connection can then be to either a right-sided or
a left-sided superior caval vein. Such interruption can also be found
with usual atrial arrangement, even when there are multiple spleens and
left bronchial isomerism.\textsuperscript{16} The intracardiac anatomy
is then usually normal.

Bilateral superior caval veins are frequent, but in the form of a
coronary sinus, usually with one or other draining through a coronary
sinus. When there is a coronary sinus, it receives the coronary venous
drainage. When the coronary sinus is absent, the coronary veins connect
directly to the atrial chambers.

The atrial septum is much better formed in left as opposed to right
isomerism. Biventricular and mixed atrioventricular connections are also
more frequent than in right isomerism, usually with a common
atrioventricular junction, as are concordant ventriculo-arterial
connections. It is much more frequent with left isomerism, therefore, to
find patterns producing relatively normal circulations. If obstruction
is found within the ventricular outflow tracts, it is usually the left
ventricle that is involved. Because of the isomeric left atrial
appendages, the sinus node is always abnormal, typically being
hypoplastic and displaced towards the atrioventricular
junctions.\textsuperscript{37}

\textbf{Surgical Management}

Optimal management of the two sub-sets remains
nebulous.\textsuperscript{14-25,38} The subsets, nonetheless, are best
segregated on the basis of right versus left isomerism. The markedly
different features will post different surgical challenges. Overall
surgical management has evolved with time. Moderately hypothermic
cardiopulmonary bypass at 32\selectlanguage{ngerman}°C, using cold blood cardioplegia, is now
the most popular technique, replacing continuous cardiopulmonary bypass
with low-flow perfusion, brief periods of deep hypothermic circulatory
arrest, and deep hypothermic circulatory arrest with selective cerebral
perfusion.\textsuperscript{14-25,38} Venous cannulation can be
problematic in both subsets because of the systemic venous anomalies.
Direct cannulation is preferred because of the likely complexity of any
intraatrial repair. The intracardiac anomalies are more likely to be
amenable to complete repair in those with left isomerism, with
biventricular repairs reported in one-third to one-half of
patients.\textsuperscript{14-25,38} Such repairs, nonetheless, often
require complex atrial and ventricular baffle
procedures.\textsuperscript{14-25,38} The complex malformations
associated with right isomerism, in contrast, usually preclude
biventricular repair.

\textbf{Pulmonary arterial banding}

Pulmonary artery banding, using conventional and absorbable bands, has
been performed as initial palliation in premature infants with low body
weight and/or severe associated non-cardiac congenital anomalies. The
lesions requiring such treatment include unbalanced complete
atrioventricular septal defects, multiple muscular septal defects, and
those with common atriums.\textsuperscript{14-25,38} These are found in
either sub-set.

\textbf{Systemic-to-pulmonary arterial shunts}

These procedures are required most frequently in those with right
isomerism. Over time, descriptions have been provided of the use of the
modified Blalock-Taussig shunt, the Waterston-Cooley shunt, and the UKC
shunt.\textsuperscript{14-25,39,40} Construction of such shunts is
usually followed by repair of totally anomalous pulmonary venous
connection, with a superior cavopulmonary connection added for those
requiring emergency intervention in the setting of a functionally
univentricular heart.\textsuperscript{14-25,39-41} Alternatively, the
shunt can be performed concomitantly with rechanneling of the totally
anomalous pulmonary venous return.\textsuperscript{15,18,41} Others have
delayed the repair of obstructed totally anomalous pulmonary venous
connection by inserting a hybrid stent.\textsuperscript{22}

\textbf{Atrial septation}

Several techniques have been described for construction of interatrial
baffles. When the left superior caval vein is unroofed, septation has
been achieved using an obliquely positioned patch. In association with
anomalous pulmonary venous return, some have used one patch for
direction of the pulmonary veins to the systemic ventricle, and a second
patch to complete atrial septation. When the orifice of the left
superior caval vein is further from the midline, the coronary sinus has
been reconstructed using a xenopericardial patch, again with a separate
patch used to complete atrial septation.\textsuperscript{14-25}

\textbf{Superior cavopulmonary connection}

This procedure has been undertaken as a prelude to creation of the
Fontan circulation in both subsets. Because of the presence of bilateral
sinus nodes in right isomerism, and the unusual location of sinus node
in left isomerism, the superior caval vein should be transected at the
level of the right pulmonary artery, retaining a small length of
superior caval wall. Dissection along the atrial roof should be
undertaken with great care to avoid potential injury to the sinus nodal
artery.\textsuperscript{37,41}

\textbf{Systemic-to-pulmonary artery shunt or superior cavopulmonary
connection or Norwood's procedure with concomitant pulmonary artery
augmentation}

Restoration of an unrestricted pulmonary arterial pathway is essential
when repairing compromised pulmonary arteries. These operations have
been described on an individualized basis.\textsuperscript{14,15,41}

\textbf{Superior cavopulmonary connection with concomitant rechanneling
of totally anomalous pulmonary venous connection}

This combination, required in the setting of right isomerism, has again
been described on an individualized basis.\textsuperscript{15,18,38}

\textbf{The Kawashima procedure}

This technique was designed for those with left isomerism and azygos
continuation of an interrupted inferior caval vein. The hepatocardiac
venous and coronary sinus blood is redirected into the left-sided atrial
chamber (Figures 6C and 6D).\textsuperscript{43}

\textbf{Extracardiac and intracardiac conduits}

Subsequent to the development of the extracardiac Fontan circulation,
this operation was employed in the setting of isomerism with systemic
venous anomalies. It was extended into its fourth generation by using a
fenestrated partly intracardiac conduit.\textsuperscript{44}

\textbf{Completion of the Fontan circulation}

In those deteriorating after a previous Glenn procedure as part of
staged palliation, or after the Kawashima repair with development of
pulmonary arteriovenous malformations, the hepatic venous return has
been redirected using either an extracardiac polytetrafluoroethylene
conduit, or a partly intracardiac fenestrated conduit (Figures 8 and
9).\textsuperscript{43-47,64} Other investigators have created brachial
arteriovenous fistulas for treatment of the pulmonary arteriovenous
malformations.\textsuperscript{8,9,43-47}

\textbf{Rechanneling of totally anomalous pulmonary venous connection}

These procedures are required in all of those with right isomerism, even
if the pulmonary veins connect to the heart. Several guidelines have
emerged. Minimal manipulation of the pulmonary veins is advised during
dissection of the pulmonary venous confluence. So as to minimize the
thickness of the anastomosis, small endocardial-to-endocardial bites are
optimal. The extracardiac confluence can usually be explored by lifting
the cardiac apex, dislocating it into the right thoracic cavity. A large
unrestrictive anastomosis can then be made by using a posterior
approach. When the connection is obstructed, routine left atrial
augmentation is usually required. This can be achieved using a
fenestrated Dacron patch. Should the obstructive connection have
resulted in suprasystemic pulmonary arterial pressures, then we prefer
adjustable ligation of the vertical vein.
\textsuperscript{48,49}Circulatory arrest has often been required in
neonates to optimize visualization. The pectinated atrial wall is an
additional complicating factor when seeking to create an unobstructed
communication with the pulmonary venous
confluence.\textsuperscript{48,49}

\textbf{Total cavopulmonary connection with concomitant rechanneling of
totally anomalous pulmonary venous connection}

This procedure has been recommended in those with right isomerism when
the totally venous connection is unobstructed.\textsuperscript{15,38}

\textbf{Rechanneling of the persistent left superior caval vein}

Techniques described include simple ligation, division and
reimplantation to the right-sided atrium, construction of an
intra-atrial, placement of an interposition graft to the to right-sided
atrium, and anastomosis of the vein to the left pulmonary
artery.\textsuperscript{19,50}

\textbf{Transcatheter approaches, or surgical ligation of major
aortopulmonary collateral arteries}

Collateral channels have been managed either by embolization or by
surgical ligation. Transcatheter angioplasty and insertion of expandable
stents have been employed for enlargement of stenotic anomalous
pulmonary veins, pulmonary arterial stenosis, and stenosed venous
circuits following cardiac
transplantation.\textsuperscript{15-18,20,22,25}

\textbf{Cardiac transplantation}

Using appropriate reconstructive techniques, orthotopic cardiac
transplantation has been performed in selected individuals with right
isomerism, a functionally single ventricle, and totally anomalous
pulmonary venous connection. The techniques include interposed spiral
saphenous vein grafts, superior and inferior intraatrial baffles, a
composite cavopericardial graft to the right brachiocephalic vein, a
diaphragmatic pericardial tunnel, and separate right and left pulmonary
venous cuffs. Dacron conduits placed between the right-sided atrium and
the left superior caval vein, along with counter-clockwise rotation of
an anastomosis to the left sided inferior caval vein, have permitted
restoration of continuity of the systemic venous
return.\textsuperscript{24,25,51-53}

\textbf{Correction of associated cardiac anomalies}

Additional associated congenital cardiac anomalies are all been treated
on their own merits.\textsuperscript{14-22}

\textbf{Outcomes in the short and long term}

Despite the advances made in diagnosis and surgical treatment, the
overall prognosis remains less than satisfactory in either the long or
the short term.\textsuperscript{14-22} To an extent, this is hardly
surprising, since right isomerism has long been recognized as one of the
worst forms of congenital heart disease. The malformations in right
isomerism, for the most part, preclude biventricular
repair.\textsuperscript{15,18,19,21-23,41,43-47} Reported mortalities
range between one-third and one-half for construction of a
systemic-to-pulmonary arterial shunt and repair of totally anomalous
pulmonary venous connection repair, while comparable mortalities have
ranged between one-third and three-quarters for functionally
univentricular repair.\textsuperscript{15-23,46} Of those in whom a
superior cavopulmonary connection had been constructed, up to
one-quarter proceeded to completion of the Fontan circulation, but even
in this group there was reported mortality of
one-fifth.\textsuperscript{15-23,42} Totally anomalous pulmonary venous
connection was identified as a poor prognostic indicator, associated
with a median age at death of of 3 months, with the addition of
pulmonary atresia resulting in a median age at death of 1
month.\textsuperscript{9} But, since totally anomalous pulmonary venous
connection is universally present in those with right isomerism, it is
likely the combination with pulmonary atresia that is the straw that
breaks the back of the camel.

Reported mortalities for those with left isomerism and functionally
univentricular repair range between one-fifth and one-third, but for
those suitable for biventricular repair, mortality has been reported
between zero and one-quarter.\textsuperscript{16,17} Of those undergoing
univentricular palliation, however, only seven-tenths are in NYHA class
I, as opposed to almost all of those suitable for biventricular
repair.\textsuperscript{15-23,55} Longer term prognosis at present is
equally depressing. At one year, 85\% of those with right isomerism are
dead, along with more than half of those with left
isomerism.\textsuperscript{15-23,55} The situation, of course, is
further tilted against those with right isomerism, since in absence of
the spleen they have an increased risk of
sepsis.\textsuperscript{15-23,55-57} In most reported series,
unsurprisingly, survival is better when the lesions permit biventricular
repair.\textsuperscript{14-23,55-58} Such biventricular repair has been
reported in a small proportion of patients with right
isomerism.\textsuperscript{15,18,19,21-23,41,43,47-49} And for those not
receiving surgical intervention, death is
inevitable.\textsuperscript{28} Incremental risk factors for death have
been identified as obstructed totally anomalous pulmonary venous
connection, restenosis of pulmonary veins, and pulmonary atresia.

\textbf{Discussion}

The evidence is now strongly in favour of discriminating between the
recognized sub-sets of so-called ``visceral heterotaxy'' on the basis of
isomerism of the atrial appendages.\textsuperscript{4-13} With the
advances now made possible through the increased resolution of
multi-detector computed tomography, and the ability to reconstruct the
three-dimensional datasets, it is possible not only to recognize the
features of the atrial appendages, but also to correlate the cardiac
findings with the arrangements of thoracic and abdominal organs. The
clinical findings endorse the conclusions long since made based on
autopsy studies. Thus, right isomerism is usually, but not universally,
accompanied by absence of the spleen. It is this feature that is
believed to render such individuals susceptible to infection. The
isomeric right appendages are the harbingers of the most severe cardiac
and complex congenital malformations.\textsuperscript{2-13} Left
isomerism is typically associated with polysplenia, but even the
presence of multiple spleens does not protect against splenic
incompetence.\textsuperscript{15-23,54}

The markedly different features of right as opposed to left isomerism
obviously pose different surgical challenges. Detailed knowledge of the
likely co-existing cardiac anomalies, therefore, is advantageous prior
to surgical intervention. Recognition of the presence of bilateral
morphologically right atrial appendages, for example, enables the
surgeon to anticipate the presence of bilateral sinus nodes. Recognition
of isomeric left appendages, in contrast, alerts to an abnormal location
of the atrial pacemaker.\textsuperscript{37,60} Appropriate precautions,
therefore, should be taken to avoid injury not only to the sinus node,
or nodes, but also their arteries.\textsuperscript{42}

In those with left isomerism, the surgeon should anticipate interruption
of the inferior caval vein. If performing a superior cavopulmonary
connection, and prior to ligating the azygos venous channel, an enlarged
azygos vein associated with an intact inferior caval vein should always
be differentiated from azygos continuation of an interrupted vein. When
the inferior caval vein connects directly to the atrial chambers, it may
connect to either the left or right-sided atrium. In left isomerism,
this should be distinguished from bilateral connection of hepatic veins.
In those with right isomerism, in contrast, a hepatic vein often
co-exists with an inferior caval vein (Figures 8 and
9).\textsuperscript{2-5,9-11}

Although the arrangement of the inferior caval vein tends to distinguish
those with left from right isomerism, this is not the case for the
superior caval vein. At least half of patients with right isomerism, and
up to two-thirds of those with left isomerism, have bilateral superior
caval veins.\textsuperscript{2-13,15,19} When bilateral superior caval
veins are present with right isomerism, each connects to the top corner
of its atrium. This can make it difficult to divert the vein to the
right-sided atrium, should this be required, or because of its short
length even to the right superior caval vein.\textsuperscript{50} In
left isomerism, in contrast, both superior caval veins are connected to
atrial chambers in the fashion of drainage through a coronary sinus,
although often unroofed.\textsuperscript{2,7,10,11} The hepatic venous
connections are of particular concern in this setting. The veins usually
connect to one atrium, but sometimes to both atriums, or to both sides
of a common atrium (Figures 7 and 8).\textsuperscript{5,7,9-13} Such
direct hepatic venous connections are not only found when the inferior
caval vein is interrupted, but also when it connects directly to one or
other atrial chamber. When performing the Kawashima procedure, search
should be made for any interconnections between the inferior caval vein
and the hepatic veins below their entry to the
heart.\textsuperscript{5,7,9-13,43-47} Preoperative demonstration of
such venous arrangements can facilitate construction of fenestrated
Fontan pathways (Figure 9).\textsuperscript{44-46}

Although not always recognised, totally anomalous pulmonary venous
connection is universal in the setting of right isomerism, since both
atrial appendages are morphologically right. Even should all pulmonary
veins connect directly to one of the atrial chambers, such connections
will be anatomically anomalous.\textsuperscript{2,3} The cardiac venous
return is often obstructed. \textsuperscript{2-5,14-22} The presence of
pectinate muscles all around the muscular atrioventricular vestibules
creates additional problems in producing an unobstructed pulmonary
venous pathway.\textsuperscript{2-15,19-22} Pulmonary venous obstruction
is the more frequent when the pulmonary arteries are hypoplastic,
atretic, or discontinuous.\textsuperscript{2-15,19-22} Severe
obstruction to pulmonary venous flow may mask the clinical importance of
the pulmonary venous anomaly.\textsuperscript{2-22} On our institute, we
continue to perform adjustable ligation of the vertical vein, routine
left atrial augmentation, and interatrial septal fenestration when we
recognise obstructive totally anomalous pulmonary venous connection, or
when we encounter suprasystemic pulmonary arterial hypertension
subsequent to weaning from bypass.\textsuperscript{48,49} It is almost
certainly the intrinsic anatomic and histopathologic differences in the
pulmonary veins of individuals with right isomerism that accounts for
the higher incidence of reoperation when compared to individuals with
lateralized atrial appendages.\textsuperscript{14,15,20,21,48,49,61-63}

The pulmonary venous connections will always be anatomically normal when
there is left isomerism, but such normally connected veins can be
bilaterally symmetrically, with two connecting to each atrium with a
morphologically left appendage.\textsuperscript{2-5,11} This produces a
significant distance between the right and left-sided pulmonary
veins,\textsuperscript{5,9-13} making for elongated and complex suture
lines for any potential intraatrial baffle.\textsuperscript{14-22} The
complexity of the required baffles can explain in part the reported
incidence of postoperative arrhythmias, which has ranged between less
than one-tenth to one-half. Also contributing to these problems are the
absence, hypoplasia, or abnormal location of sinus node, along with
abnormalities in the pathways for atrioventricular
conduction.\textsuperscript{14-21,59,60}

Another well recognized problem in the setting of left isomerism is the
development of pulmonary arteriovenous malformations following the
Kawashima operation, seen in up to three-fifths of cases (Figure
10).\textsuperscript{45,46,64} This is attributed to isolation of the
lungs from exposure to hypothetical hepatic factors. Redirection of the
hepatic venous return to the systemic venous circuit during completion
of the Fontan circulation has been shown to result in subsequent
resolution.\textsuperscript{45,46,64}

Within the overall group, regurgitation of the common atrioventricular
valve is a known risk factor for postoperative mortality, particularly
after functionally univentricular repair. A systemic-to-pulmonary
arterial shunt is known to cause volume overload, aggravating the
regurgitation, and increasing mortality following completion of the
Fontan circulation. \textsuperscript{15,21,43-47} This has led to
suggestions that the common valve be repaired or replaced before
completion of the operations.\textsuperscript{41,45-47} Cardiac
transplantation also represents a significant technical challenge. This
may reflect previous palliative procedures, but is further exacerbated
by the complex systemic and pulmonary venous
anomalies.\textsuperscript{24,25} Even though the technical issues have
largely been resolved, transplantation in the setting of isomerism
remains associated with increased postoperative complications. Early and
late survival is poor compared to other forms of congenital cardiac
diseases.\textsuperscript{24,25,51-53}



\textbf{Conclusions}

Based on the information available to us from the literature, and
including our own experience, we are convinced that multimodality
imaging is now capable of characterizing and delineating the precise
anatomical details of the two sub-sets of individuals born with isomeric
atrial appendages. These investigations should now permit the mandatory
assessment of the pulmonary venous return required in the setting of
right isomerism to unmask concealed pulmonary venous obstruction. In
those with left isomerism, such investigations should now delineate the
patterns of drainage of the inferior caval and hepatic venous systems.
Given the ongoing high mortalities of those requiring a combination of
shunting procedures, or functionally univentricular repair, it seems
prudent to reassess the conventional strategies for management. In
particular, the option of cardiac transplantation should now be
systematically evaluated as an alternative pathway of management for
those deemed to be at high risk.



\textbf{Author's contribution}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\textbf{Author's name} & \textbf{Concept/ design} & \textbf{Data
analysis/ interpretation} & \textbf{Drafting article} & \textbf{Critical
revision} & \textbf{Approval of article} & \textbf{Statistics} &
\textbf{Funding} & \textbf{Data Collection}\tabularnewline
\midrule
\endhead
Ujjwal Kumar Chowdhury & ? & ? & ? & ? & ? & ? & - & ?\tabularnewline
Robert H. Anderson & ? & ? & ? & ? & ? & ? & - & ?\tabularnewline
Diane E. Spicer & ? & ? & ? & ? & ? & ? & - & ?\tabularnewline
Lakshmi Kumari Sankhyan & ? & ? & ? & ? & ? & ? & - & ?\tabularnewline
Niraj Nirmal Pandey & ? & ? & ? & ? & ? & - & - & ?\tabularnewline
Shikha Goja & ? & ? & ? & ? & ? & - & - & ?\tabularnewline
Palleti Rajasekar & - & ? & ? & ? & ? & - & - & ?\tabularnewline
Balaji Arvind & - & ? & ? & ? & ? & - & - & ?\tabularnewline
Doniparthi Pradeep & - & ? & ? & ? & ? & - & - & ?\tabularnewline
\bottomrule
\end{longtable}



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\textbf{Figure Legends}

Figure 1. The echocardiographic image in the apical 4 chamber view shows
both atrial appendages to be morphological left (red asterisks). Note
the dilated coronary sinus (CS). The inset shows the subcostal axial
view, revealing a venous channel (yellow asterisk) coursing posterior to
the descending thoracic aorta (red asterisk). This is the interrupted
inferior caval vein. The atrioventricular connections are mixed with
right-handed ventricular topology (RV and LV). The modified high
parasternal view in panel B shows the continuation of the inferior caval
vein through the azygos vein to the left superior caval vein.
Abbreviations : LA, left atrium; LSCV, left superior caval vein; LV,
left ventricle; RA, right atrium; RV, right ventricle{]}

Figure 2: Volume rendered images (A, anterior view, and B, left anterior
oblique view) in a patient with right isomerism showing both appendages
to be morphologically right (*right sided morphologically right
appendage, **left sided morphologically right appendage). Panel C,
showing a posterior view, and panel D, a right lateral view, show the
all four pulmonary veins draining at the junction of superior caval vein
(SCV) with right atrium (RA) (black arrow in D).{]}

Figure 3: Axial computed tomographic images in a patient with right
isomerism show, in panel A, a transverse midline liver. Panel B shows
bilateral right bronchial morphology. The coronal image in panel C shows
bilateral superior caval veins, each draining to its own atrium (R:
right-sided morphologically right atrium; L: left-sided morphologically
left atrium). The volume rendered images in panels D and E show the
right-sided (*) and left-sided appendages (**), both morphologically
right. As seen in panel F, all pulmonary veins (arrowheads) drain to the
right-sided atrium

Figure 4: The volume rendered images, shown in panel A in right anterior
oblique view, in panel B in left anterior oblique view, and in panel C
in posterior view, show bilateral appendages of right morphology, with
all pulmonary veins joining the right-sided atrium. Abbreviations: RA:
right-sided atrium; LA: left-sided atrium; RV: right ventricle; LV: left
ventricle; RSPV: right superior pulmonary vein; RIPV: right inferior
pulmonary vein; LSPV: left superior pulmonary vein; LIPV: left inferior
pulmonary vein, *right sided morphologically right atrial appendage,
**left sided morphologically right atrial appendage{]}

Figure 5: Panels A and B show axial images, and Panels C and D show
volume rendered images from a patient with right isomerism and pulmonary
atresia. All the pulmonary veins (indicated by arrowheads) are connected
to the right-sided atrium with a morphologically right appendage (RA).
Note the co-existing defect in the oval fossa (white asterisk in B) and
the perimembranous ventricular septal defect (black asterisk in B and
C). Oblique axial image, as seen in panel E, shows pulmonary atresia
(black arrow) with good-sized confluent pulmonary arteries. Oblique
coronal image, seen in panel F, shows a patent arterial duct (indicated
by star) feeding the pulmonary arteries. Abbreviations : RAA: right
atrial appendage; LA: left-sided atrium; RV: right ventricle; LV: left
ventricle; LPA: left pulmonary artery; RPA: right pulmonary artery.{]}

Figure 6:~ Panel A shows a coronal image, and panel B a volume rendered
image, from a patient with left isomerism. There is azygos continuation
of the inferior caval vein, with the azygous vein (*) draining into the
superior caval vein (SCV). Panels C through E show volume-rendered
images subsequent to repair using the Kawashima procedure, with the
superior caval vein connected to the pulmonary arteries. Abbreviations :
RPA: right pulmonary artery; LPA: left pulmonary artery.

Figure 7: Panel A is an axial image from a patient with left isomerism,
showing multipler spleens (yellow circle). The coronal minimal intensity
projection image in panel B shows left bronchial isomerism. The volume
rendered images seen in panel C, an anterior view, shows the hepatic
veins (arrowed) draining into the right-sided atrium, which has a
morphologically left appendage. Panel D, a sagittal image, demonstrates
azygos (*) continuation of the inferior caval vein into the superior
caval vein (SCV).

Figure 8: The volume rendered image (Panel A) from a patient with left
isomerism shows hemiazygos (black arrows) continuation of the inferior
caval vein into the left-sided superior caval vein (LSCV), which has
been anastomosed~to the pulmonary artery. Panel B shows separate hepatic
veins (arrowheads) rerouted to the right pulmonary artery (RPA) via a
graft (*). The maximum intensity projection image in panel C shows a
pulmonary arteriovenous malformation (thick white arrow) in the left
lower lobe.

Figure 9: The volume rendered image (Panel A) and the oblique coronal
images (Panels B and C) are from a patient with left isomerism in whom
the left-sided superior caval vein (LSCV) has been anastomosed to the
left pulmonary artery (RPA). The hepatic veins (arrowheads) and the
inferior caval vein have been connected to the right pulmonary artery
(RPA) via a conduit whiuch is partly extracardiac and partly
interatrial.

Figure 10: The volume rendered images, shown in a posterior view (panel
A), a left anterior oblique view (panel B), and an anterior view (panel
C), are from a postoperative patients with left isomerism who developed
pulmonary arteriovenous malformations. There is hemizaygos (*)
continuation of the inferior vena cava into the superior caval vein
(SCV), which in turn has been anastomosed to the pulmonary arteries. The
maximum intensity projection image in panel D shows a pulmonary
arteriovenous malformation (yellow arrow) in the left lower lobe.
Abbreviations : RPA: right pulmonary artery; LPA: left pulmonary artery.\selectlanguage{english}
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