Atrial Appendages

As discussed briefly earlier, the basis of segregating isomerism should be the morphology of the atrial appendages. The morphology of the atrial appendages is the best guide to atrial arrangement not only in patients with isomerism, but also in the overall setting of the congenitally malformed heart. Whereas isomerism was historically segregated on the basis of splenic anatomy, with subsets described in terms of polysplenia or asplenia, it is now known that the morphology of the appendages is of greater utility in identifying more consistent and homogenous patient cohorts for whom care strategies can be directed. Additionally, these patient cohorts, based on atrial appendage morphology, appear to be more aligned with the molecular underpinnings of isomerism. This is based on studies done by Uemura and colleagues, who demonstrated that the syndromic clustering of associated features is greater when assessed on the basis of appendage morphology. Additionally, studies of knockout mice demonstrate that similar genetic mutations result in consistent findings in regard to the morphology of the appendages, although these are not always consistent with splenic morphology. The assignment of “leftness” or “rightness” of the appendages has also undergone an evolution in thinking. Until relatively recently the external features of the appendage were used to define its morphology. However, although the morphologically right atrial appendage is usually broad and pyramidal in shape in comparison with the left atrial appendage, which is narrower and tubular, these external characteristics can be influenced by hemodynamic conditions. Consequently, we now use the internal features, specifically the extent of the pectinate muscles, to define appendage morphology. The pectinate muscles of the right atrial appendage spill outside of the atrial appendage and extend around the entirety of the atrioventricular junction ( Fig. 67.1 ). The pectinate muscles of the left atrial appendage, in contrast, are confined to its tubular component and do not extend around the atrioventricular junction so as to reach the cardiac crux. It should be noted, however, that appendage isomerism is not equivalent to atrial isomerism. The overall atrial chambers, including the venoatrial connections, are not isomeric, although the arrangements have features suggestive of isomerism. The atrial appendages, in contrast, when assessed according to the extent of the pectinate muscles, unequivocally are.

Images from a necroscopy specimen from a patient with right isomerism. (A) The right atrial appendage has been opened to demonstrate the pectinate muscles, which spill outside of the atrial appendage and extend to the atrioventricular junction. (B) The left-sided atrial appendage has been opened to demonstrate the pectinate muscles, which spill outside of the atrial appendage and extend around the atrioventricular junction as well.

That said, there are some significant clinical challenges when atrial morphology is defined in this way. Definition of pectinate morphology in the working heart is all but impossible in everyday practice. For example, the atrial appendages are difficult to image using transthoracic echocardiography, and, although transesophageal echocardiography can usually describe appendage shape and size, it is rare that the extent of the pectinate muscles can be defined with clarity. Magnetic resonance and computed tomography imaging can allow for visualization of the pectinate muscles ( Fig. 67.2 ), but these techniques are expensive and not used in day-to-day practice. Paradoxically, the simple chest radiograph may be the most reliable surrogate because there is remarkable concordance between bronchial and appendage morphology. Even so, there are many other features that align with either right or left isomerism and that can be used to determine isomerism sidedness ( Table 67.1 ), which will be discussed in detail later.

A three-dimensional magnetic resonance reconstruction from a 10-month-old with right isomerism demonstrating external visualization of the atrial appendages. Although external appendage morphology is not the gold standard to determine atrial appendage morphology, this patient has atrial appendages that both have a broad, pyramidal shape that is consistent with right isomerism. The extent of the pectinate muscles can be delineated by magnetic resonance imaging, although this can be quite difficult. Computed tomography reconstructions are easier to produce to demonstrate the extent of the pectinate muscles.

Cardiac Morphology

Outside of the atrial appendages, the remainder of the cardiac components also demonstrate characteristic findings. A right-sided superior caval vein is present in approximately 80% of those with either right or left isomerism. A left-sided superior caval vein is present in approximately 50% of those with either right or left isomerism. A left-sided superior caval vein may be present in isolation or concurrently in the presence of a right-sided superior caval vein. If a left superior caval vein is present, it may drain via the coronary sinus or directly to the roof of the left-sided atrium. This difference is of importance because the coronary sinus is uniquely a left-sided structure and so is always absent in the setting of right isomerism. Under such circumstances a left-sided superior caval vein, if present, will always connect directly to the atrial roof. In the setting of right isomerism no coronary sinus will be present, and the cardiac veins will drain directly to the atrium.

Defining the disposition of the inferior caval vein is the mainstay of echocardiographic diagnosis. In isomerism the abdominal great vessels are usually lateralized together on the right or left side of the spine. Interruption of the inferior caval vein is characteristic of left isomerism. When the inferior caval vein is interrupted, it will either drain into an azygos or hemiazygos vein, which then drains into the right- or left-sided superior caval vein, respectively. Consequently, the echocardiogram in left isomerism will show lateralized abdominal great vessels with the vein posterior to the aorta, whereas in right isomerism (where the inferior caval vein is usually uninterrupted) the vein will be anterior to the aorta. It should be remembered that there is an intact intrahepatic inferior vena cava in approximately 10% of patients with left isomerism, but even so, there is often a dominant azygous vein draining ipsilateral and posterior to the aorta. This has implications when it comes to staged palliation of those with functionally univentricular hearts, with regard to timing of the second-stage operation and postoperative physiology. In patients with left isomerism the bidirectional Glenn procedure, in which the superior caval vein or veins are anastomosed to the pulmonary arteries, will incorporate the return from the inferior caval vein when there is azygos or hemiazygous continuation. This second stage of palliation is known as the Kawashima operation and leaves only the hepatic veins to be redirected to the pulmonary arteries at the time of Fontan completion.

The hepatic veins can return to the heart in a number of ways in those with isomerism. In left isomerism a little over half of patients will have all hepatic veins draining directly to the right-sided atrium. Approximately 20% of patients will have hepatic veins draining into the left-sided atrium, and another 20% will have hepatic veins draining in bilateral fashion to both the right- and left-sided atrial chamber. Only 10% will have hepatic venous drainage to the inferior caval vein. In right isomerism the hepatic veins drain into the inferior caval vein in 75% of patients and directly to the right-sided atrium in 25% of patients.

The pulmonary venous drainage and connection is also variable in those with isomerism. Necessarily, the pulmonary venous connections are always anomalous in right isomerism because there is no morphologic left atrium. The connections can be cardiac, infradiaphragmatic, supracardiac, or mixed, and defining the exact path of drainage of each pulmonary vein is crucial in these patients. As is seen outside of the setting of isomerism, obstruction to the pulmonary venous return is anticipated when there is an infradiaphragmatic connection and also can be produced by the bronchopulmonary vice or a course under the bronchus itself when the connection is supracardiac. This can add to the complexity of surgical intervention, impact the need for reintervention, and influence mortality during long-term follow-up.

In left isomerism, direct cardiac connections of the pulmonary veins to the atriums is expected, either bilateral or lateralized to one or the other left atrium. To the best of our knowledge, only a single case of extracardiac anomalous connection has been described in the setting of left isomerism. Consequently, although it remains important to define exactly the mode of connection of the pulmonary veins, when planning septation of the atriums for example, their disposition has much less impact on outcomes than in patients with right isomerism.

At least four-fifths of those with either right or left isomerism will have a common atrioventricular junction, also referred to as an atrioventricular septal defect. This is more frequently observed in patients with right isomerism, who nearly always have a common atrioventricular junction. The presence of a tongue of tissue connecting the superior and inferior bridging leaflets in the setting of a common atrioventricular junction, thereby creating two separate orifices, is more frequent in those with left isomerism. With respect to the ventriculoarterial connections, almost 75% of those with left isomerism will have concordant connections, albeit oftentimes with mirror-imaged spiraling of the aorta relative to the pulmonary trunk. Those with right isomerism most frequently have double-outlet right ventricle or discordant ventriculoarterial connections, typically with an anterior aorta, which may be right- or left-sided depending on the ventricular topology.

Ventricular topology can be either left handed or right handed in either form of isomerism. Biventricular atrioventricular connections, however, are much more frequent in the setting of left isomerism, whereas double inlet through a common atrioventricular valve is more frequent in those with right isomerism. Those with right isomerism are more likely to have a true solitary ventricle, as evidenced by failure to identify a second slit-like incomplete ventricle at the time of necropsy. Abnormal coronary arterial patterns are noted in approximately 20% of those with isomerism, with single coronary artery being the most frequent variant.

Conduction System and Arrhythmias

The conduction system is expected to be malformed in those with isomerism. Twin sinus nodes are typically present in those with right isomerism, but de novo atrial arrhythmia is rare. The sinus node is universally hypoplastic in the setting of left isomerism. If found, it is abnormally located at a closer position relative to the atrioventricular junctions. Consequently, an abnormal P-wave axis is usual in left isomerism.

Twinning of the atrioventricular nodes can also be found. Either or both of these nodes may connect to the ventricular conduction system, providing the possibility of a sling of conduction tissue to form between them, providing the substrate for a reentry type tachycardia. This is more frequent in those with right isomerism. If one node does not connect to the ventricular conduction system, it is more frequently the anterior node. This has clinical consequences and may influence ablation plans. Discontinuity between both nodes and the ventricular system is more frequent in left isomerism, producing complete atrioventricular block.

A large proportion of children and adults with isomerism will have arrhythmias. Those with right isomerism are more likely to have supraventricular tachycardias during long-term follow-up, although whether this is related to intrinsic propensity or reflective of a greater extent of atrial surgery (e.g., repair of anomalous pulmonary venous connection, higher frequency of Fontan palliation) is not known. Nonetheless, electrophysiology studies and ablations can be effectively conducted in those with isomerism, particularly before Fontan completion. Those with left isomerism are more likely to have atrioventricular block, and this is the commonest cause of fetal demise. Postnatally those with left isomerism and atrioventricular block may or may not require a pacemaker. Some patients tolerate a predominantly junctional rhythm without any significant clinical issues. However, all patients with left isomerism require careful and regular follow-up of their atrioventricular conduction, with annual evaluation by Holter monitoring.

Myocardial Fibrosis and Ischemia

Approximately 16% of hearts from those with isomerism will demonstrate some degree of myocardial fibrosis at the time of necropsy. Approximately 10% will demonstrate evidence of myocardial ischemia. This early development of fibrosis and ischemia then leads to the question as to whether adults with isomerism are at an increased risk for myocardial infarction. Although the location of myocardial infarction differs slightly between those with and without isomerism, the age of myocardial infarction, ability to successfully stent the coronary lesions, and mortality from myocardial infarction do not differ in those with isomerism when compared to those without.

Impact on Surgical Palliation

Approximately 85% of those with isomerism will require functionally univentricular palliation, whereas the remainder will require some form of biventricular repair. Functionally univentricular neonatal repairs may consist of either a Norwood procedure, pulmonary artery banding, or systemic to pulmonary shunt with or without pulmonary vein repair. Some patients require no intervention initially if pulmonary stenosis is present with an adequate balance of the ratio of pulmonary and systemic blood flow. Careful monitoring during the neonatal period and early infancy will obviously be required, particularly if there is associated anomalous pulmonary venous return. This is important because data from Toronto show that if pulmonary venous repair can be delayed beyond the third month of life, the outcomes are far superior compared with neonatal intervention.

The second and third stages of palliation can also be somewhat different in that the second stage could be a bidirectional Glenn procedure, a bilateral bidirectional Glenn procedure, or a Kawashima procedure with or without a contralateral Glenn procedure. For the latter, given that such surgery directs over 85% of the systemic venous return to the lungs, it may be advantageous to delay surgery beyond the usual 3- to 6-month window that is usually chosen for “traditional” bidirectional Glenn procedures, to allow for greater pulmonary artery growth and an optimally low pulmonary vascular resistance.

The third palliation is usually a Fontan completion or, in patients with left isomerism, a hepatic vein to pulmonary artery connection. Both procedures can be technically challenging. In right isomerism care must be taken to avoid the extracardiac conduit from impinging on the pulmonary veins, and in some cases an intraatrial tube graft is preferred. Similarly, in left isomerism routing of the hepatic veins to the pulmonary artery can be technically challenging, especially if the hepatic veins come into different sides of the atrial septum, or “physiologically challenging” if the hepatic venous flow is directed predominantly to one pulmonary artery because this may increase the propensity to form pulmonary atrioventricular malformations on the contralateral side (see later).

One of the more challenging issues with single-ventricle palliation in these patients is the function of the common atrioventricular valve because few consistently effective techniques exist. A detailed discussion of the usually individualized approach to valve repair is beyond the scope of this chapter, but suffice it to say that both short- and long-term outcomes will be significantly impacted by the degree of residual regurgitation and/or stenosis, particularly in those pursuing a univentricular pathway, but also in those undergoing biventricular repair.

Biventricular repairs will often include atrioventricular septal defect repair, baffling of an intraventricular communication in the setting of double-outlet right ventricle and complex intraatrial tunnels. These procedures can be quite successful in carefully selected patients. The technical success of these repairs in the short term should rarely be an issue under those circumstances; however, the long-term problems associated with atrioventricular valve failure or stenosis of the frequently required complex surgical tunnels, be they intraatrial or intraventricular, needs to be kept in mind when deciding whether to pursue a two-ventricle repair.

It should come as no surprise, given the complexities discussed earlier, that there is a significant impact of isomerism on the outcomes of surgical palliation, particularly in the setting of functionally univentricular palliation. Hospitalization for stage I palliation is often longer in those with isomerism, and patients are more likely to either remain inpatient during the interstage period or have more interstage hospitalizations. Mortality before stage I palliation and during the interstage period is also greater in those with isomerism. However, length of stay, cost, frequency of extracorporeal oxygenation, and frequency of mortality does not differ for stage II palliation between those with and without isomerism.

The outpatient trajectory after stage II palliation, however, can differ between those with and without isomerism. Those with left isomerism in particular are more likely to develop pulmonary arteriovenous malformations, leading to progressive hypoxia. Up to 33% of patients with left isomerism will develop such pulmonary arteriovenous malformations, believed to be due to the lack of hepatic factor reaching the lungs from the hepatic veins ( Fig. 67.3 ). In those patients who develop pulmonary arteriovenous malformations after the Kawashima procedure, completion of the Fontan circulation can lead to regression of these arteriovenous malformations by introducing hepatic factor to the lungs once again, a process that can take approximately 6 months. Teams have to keep in mind the technical issues with trying to evenly distribute the hepatic factor when completing the Fontan, especially when there is a bilateral bidirectional Glenn or a Glenn and a Kawashima procedure.

Left pulmonary angiography in a 5-year-old with left isomerism after stage II palliation (left) . The granularity in her left pulmonary vasculature was highly concerning for severe burden of pulmonary arteriovenous malformations, which were then confirmed by saline contrast echocardiography (right) . Similar findings were noted with the right lung as well.

Although there is limited published experience with the Y -graft Fontan, this approach to the Fontan has been demonstrated, by several studies based on computer modeling and small clinical cohorts, to provide a decrease in Fontan power loss and provide a more equal distribution of hepatic blood flow to both lungs. Pre-Fontan magnetic resonance imaging studies with four-dimensional flow analysis and computed flow dynamics are important to design the Y -graft properly, with limb size of the Y -graft, caliber of the branch pulmonary arteries, pulmonary artery resistances, and superior caval flow dynamics being of great importance when planning a Y -graft. This as a practical approach for most programs may be limited. Alternative strategies to direct the hepatic veins towards the azygous vein, rather than directly into the pulmonary arteries, are also being explored.

After Fontan completion, isomerism has been demonstrated to be associated with increased length of hospital stay, cost of stay, and need for extracorporeal membrane oxygenation. Isomerism does not appear to be associated with increased inpatient mortality during the Fontan hospitalization.

There is minimal published data with regard to cardiac transplantation in the setting of isomerism, although anecdotally these children do tend to tolerate transplantation well. As is the case with any heart transplantation, success is based on the overall condition of the patient. Patients with isomerism, given their other associated pathologies, must be thoroughly evaluated for pulmonary arteriovenous malformations, hepatic dysfunction, renal dysfunction, immune issues, and severe neurodevelopmental delay. Although complex anatomy such as systemic venous abnormalities, pulmonary abnormalities, and rightward cardiac apex are relative contraindications to transplantation, at most congenital centers there are really no anatomies that would exclude these patients from cardiac transplantation.