**2. Anatomy**

The most common anatomy of ccTGA is that of {S,L,L}, representing atrial and visceral situs solitus (right-sided inferior and superior vena cavae returning deoxygenated blood to a right sided atrium), L-looped ventricles (the morphologic LV with mitral valve positioned on the right), and L-transposed great arteries (aorta arising off the left-sided morphologic RV and therefore situated anterior and leftward of the pulmonary artery). The RV serves as the systemic ventricle and, in the absence of other defects, oxygen saturation is normal. The most common positions of the heart in the chest are levocardia (apex to the left) or mesocardia (midline). Patients with levo- or mesocardia and visceral situs inversus have a high likelihood of ccTGA and therefore must carefully by assessed for atrial, ventricular, and arterial concordance. Dextrocardia, in which the apex of the heart is to the right, occurs in approximately 20% of patients (Graham & Markham, 2010). In cases of dextrocardia with mirror-image anatomy the anatomic designation is {I,D,D}.

### **2.1 Associated defects**

The most common associated defects in ccTGA are ventricular septal defects (VSDs), which occur in 60-80% of cases, pulmonary stenosis (PS) in 30-50%, and tricuspid valve (TV) anomalies in 14-56%. The VSDs are usually large, perimembranous, and subpulmonary in location. Muscular inlet defects as well as multiple VSDs may also be seen. Pulmonary stenosis, more appropriately referred to as left ventricular outflow tract obstruction

Congenitally Corrected Transposition of the Great Arteries 163

The coronary arteries are inverted in ccTGA, as described by Ismat et al. (2002). The most common coronary positions in {S,L,L} hearts are a right coronary artery off of the left posterior aortic cusp and a left common coronary artery off the right anterior cusp. Just as the morphologic LV is situated on the right side of the heart, the morphologic left coronary artery arises off the right aortic sinus. It is this right-sided coronary that bifurcates into the anterior descending artery, which lies in the interventricular groove, and the circumflex branch that runs posterior to the heart through its course in the right AV sulcus. Additional rare anomalies have been described in which both main coronaries arise from a single ostia or one main coronary gives rise to the other (i.e., anterior descending off the right coronary artery) (Hornung & Calder, 2010; Ismat et al., 2002). The cardiac veins seem to correspond to ventricular and coronary anatomy as described in a pathological series by Bottega et al (2009). Although the coronary sinus emptied as normal into the right atrium, dilated Thebesian veins and large collaterals were commonly noted on ccTGA specimens. Venous collateralization was noted between the two ventricles, allowing the morphologic LV to drain via Thebesian veins or collaterals to the coronary sinus. These venous anomalies are thought to be of benefit in providing access to both ventricles in some percutaneous

The conduction system often consists of dual AV nodes and inversion of AV bundles. An increasing incidence of AV block, at a rate of approximately 2% per year, occurs even in the absence of surgical repair and is more likely in the presence of an intact ventricular septum (Daliento et al., 1986; Huhta et al., 1983). Anderson et al. (1974) consistently demonstrated the finding of an anterior and right-sided AV node that was situated anterolateral to the mitral-pulmonary valve junction. This node connects to the morphologic (right-sided) LV by a descending bundle of conducting tissue that travels anterior and lateral to the pulmonary outflow tract. The bundle branches are inverted, each typical of the morphologic ventricle they serve. In the presence of a subpulmonary VSD the descending AV bundle is located on the anterosuperior and anteroinferior borders of the defect. This is in contrast to concordant hearts {S,D,S} in which the conduction bundle travels along the posteroinferior margin of the VSD. Many ccTGA patients also have a posteriorly-situated AV node, which is often hypoplastic, in addition to a functional anterior node. Depending on the alignment of the interatrial and interventricular septae this posterior node may or may not have connections to the ventricles. Patients with appropriate alignment of the atrial and ventricular septae may be more likely to have two AV nodes with corresponding conduction bundles present. Invading fibrosis of the proximal AV node bundle as well as distal conduction bundles has been described on pathological specimens from older patients with correlating electrocardiogram (ECG) findings of complete heart block, suggesting fibrotic invasion is

involved in the development of AV block (Anderson et al., 1974; Daliento et al., 1986).

The incidence of ccTGA in patients with congenital heart disease (CHD) is approximately 0.5% with a slight male predominance (Graham & Markham, 2010; Piacentini et al., 2005). Although a specific genetic defect is yet to be defined for ccTGA, the recurrence risk of d-

**2.2 Coronary arteries and cardiac veins** 

procedures (Bottega et al, 2009).

**3. Incidence and genetics** 

**2.3 Conduction system** 

(LVOTO), may be caused by fibromuscular tissue, valvar stenosis, or aneurysmal tissue of the membranous ventricular septum. The associated combination of LVOTO and VSD represents the largest group of ccTGA patients. TV anomalies occur along a spectrum of which an Ebstein-like anomaly is often the most clinically severe. Furthermore, as the TV is subjected to systemic pressures, even normally formed valves display progressive regurgitation with age. Less common defects occurring in association with ccTGA include atrial septal defect, patent ductus arteriosus, pulmonary atresia, double-outlet RV, aortic regurgitation, mitral valve abnormalities, and subaortic stenosis (Graham & Markham, 2010; Hornung & Calder, 2010; Van Praagh et al., 1998).

Fig. 1. Congenitally corrected transposition of the great arteries (ccTGA) with ventricular septal defect (VSD). (With permission from Springer Science + Business Media: *Current Treatment Options in Cardiovascular Medicine*, Congenitally Corrected Transposition of the Great Arteries: An Update, Vol. 9, 2007, pp. 405-413, Graham, T.P., Markham, L., Parra, D.P., & Bichell, D., Figure 1).

#### **2.2 Coronary arteries and cardiac veins**

162 Congenital Heart Disease – Selected Aspects

(LVOTO), may be caused by fibromuscular tissue, valvar stenosis, or aneurysmal tissue of the membranous ventricular septum. The associated combination of LVOTO and VSD represents the largest group of ccTGA patients. TV anomalies occur along a spectrum of which an Ebstein-like anomaly is often the most clinically severe. Furthermore, as the TV is subjected to systemic pressures, even normally formed valves display progressive regurgitation with age. Less common defects occurring in association with ccTGA include atrial septal defect, patent ductus arteriosus, pulmonary atresia, double-outlet RV, aortic regurgitation, mitral valve abnormalities, and subaortic stenosis (Graham & Markham, 2010;

Fig. 1. Congenitally corrected transposition of the great arteries (ccTGA) with ventricular septal defect (VSD). (With permission from Springer Science + Business Media: *Current Treatment Options in Cardiovascular Medicine*, Congenitally Corrected Transposition of the Great Arteries: An Update, Vol. 9, 2007, pp. 405-413, Graham, T.P., Markham, L., Parra, D.P.,

Hornung & Calder, 2010; Van Praagh et al., 1998).

& Bichell, D., Figure 1).

The coronary arteries are inverted in ccTGA, as described by Ismat et al. (2002). The most common coronary positions in {S,L,L} hearts are a right coronary artery off of the left posterior aortic cusp and a left common coronary artery off the right anterior cusp. Just as the morphologic LV is situated on the right side of the heart, the morphologic left coronary artery arises off the right aortic sinus. It is this right-sided coronary that bifurcates into the anterior descending artery, which lies in the interventricular groove, and the circumflex branch that runs posterior to the heart through its course in the right AV sulcus. Additional rare anomalies have been described in which both main coronaries arise from a single ostia or one main coronary gives rise to the other (i.e., anterior descending off the right coronary artery) (Hornung & Calder, 2010; Ismat et al., 2002). The cardiac veins seem to correspond to ventricular and coronary anatomy as described in a pathological series by Bottega et al (2009). Although the coronary sinus emptied as normal into the right atrium, dilated Thebesian veins and large collaterals were commonly noted on ccTGA specimens. Venous collateralization was noted between the two ventricles, allowing the morphologic LV to drain via Thebesian veins or collaterals to the coronary sinus. These venous anomalies are thought to be of benefit in providing access to both ventricles in some percutaneous procedures (Bottega et al, 2009).

#### **2.3 Conduction system**

The conduction system often consists of dual AV nodes and inversion of AV bundles. An increasing incidence of AV block, at a rate of approximately 2% per year, occurs even in the absence of surgical repair and is more likely in the presence of an intact ventricular septum (Daliento et al., 1986; Huhta et al., 1983). Anderson et al. (1974) consistently demonstrated the finding of an anterior and right-sided AV node that was situated anterolateral to the mitral-pulmonary valve junction. This node connects to the morphologic (right-sided) LV by a descending bundle of conducting tissue that travels anterior and lateral to the pulmonary outflow tract. The bundle branches are inverted, each typical of the morphologic ventricle they serve. In the presence of a subpulmonary VSD the descending AV bundle is located on the anterosuperior and anteroinferior borders of the defect. This is in contrast to concordant hearts {S,D,S} in which the conduction bundle travels along the posteroinferior margin of the VSD. Many ccTGA patients also have a posteriorly-situated AV node, which is often hypoplastic, in addition to a functional anterior node. Depending on the alignment of the interatrial and interventricular septae this posterior node may or may not have connections to the ventricles. Patients with appropriate alignment of the atrial and ventricular septae may be more likely to have two AV nodes with corresponding conduction bundles present. Invading fibrosis of the proximal AV node bundle as well as distal conduction bundles has been described on pathological specimens from older patients with correlating electrocardiogram (ECG) findings of complete heart block, suggesting fibrotic invasion is involved in the development of AV block (Anderson et al., 1974; Daliento et al., 1986).

#### **3. Incidence and genetics**

The incidence of ccTGA in patients with congenital heart disease (CHD) is approximately 0.5% with a slight male predominance (Graham & Markham, 2010; Piacentini et al., 2005). Although a specific genetic defect is yet to be defined for ccTGA, the recurrence risk of d-

Congenitally Corrected Transposition of the Great Arteries 165

The authors concluded that severe TV insufficiency leading to RV dysfunction has the greatest impact on long-term survival in both operated and unoperated patients. In patients who underwent surgical intervention for ccTGA, 20-year survival rate was 90% for patients with competent TVs, whereas survival was only 35% for patients with severe TV insufficiency. Furthermore, patients who were diagnosed with severe TV insufficiency demonstrated a rapid deterioration in clinical status with RV failure occurring on average 5 years after onset of insufficiency (Prieto et al., 1998). Overall natural history in the ccTGA patient without associated defects is promising, as patients may remain relatively asymptomatic through early and mid-adulthood. However the frequent development of complications in the 4th and 5th decades often culminates in the progressive development of RV (systemic) dysfunction and heart failure, requiring aggressive medical management and

Just as the natural history is largely dependent on defects associated with ccTGA, so is

Fetal diagnosis of many forms of CHD continues to improve. However the fetus with ccTGA and mild or no additional intracardiac anomalies may be overlooked by routine ultrasound screening. Distinct features notable on prenatal ultrasound that may improve detection of ccTGA are parallel course of the great arteries in combination with dextrocardia, abnormal insertion of the papillary muscles, and/or an abnormal TV (McEwing & Chaoui, 2004; Paladini et al., 2006; Shima et al., 2009). A retrospective review by Wan et al. found no difference in the number of cardiac interventions, timing of surgery, or survival between a cohort of ccTGA patients diagnosed prenatally (n = 14) and postnatally (n = 26). However, because 70% of this cohort required cardiac intervention prior to 3 years of age, the authors suggest prenatal diagnosis is important for preparation and counseling of the family (2009). A recent review of 11 cases of fetal ccTGA diagnoses describes the use of four-dimensional echocardiography and spatiotemporal image correlation (STIC), in which the relationship of the great arteries can be assessed in several different orthogonal planes by placement of a reference dot on images reconstructed from

Diagnoses of infants and children may occur after murmur evaluation, as VSDs are commonly associated lesions. In cases of large VSDs or severe TV regurgitation, some infants may present in CHF with diaphoresis, pallor, tachypnea, inability to gain weight, hepatomegaly, and a gallop on exam. Auscultation of the ccTGA patient may also reveal a loud, single second heart sound (S2) at the left 2nd intercostal space, with absence of S2 over the right 2nd intercostal space (Friedberg & Nadas, 1970). The presence of VSD combined with LVOTO may lead to a cyanotic presentation from decreased pulmonary blood flow. However, some degree of LVOTO may be protective of the lung bed in patients with large VSDs, and may delay a CHF presentation despite the normal decrease in pulmonary

possible surgical intervention (Presbitero et al., 1995).

timing of presentation and diagnoses.

acquired volume data sets (Zhang et al., 2011).

**5.2 Early presentation and diagnosis** 

vascular resistance.

**5. Diagnosis** 

**5.1 Prenatal diagnosis** 

TGA for siblings of ccTGA patients is 2.6% with an overall recurrence risk of 5.2% for ccTGA siblings to have some type of congenital heart defect (Piacentini et al., 2005). A recurrence risk of >5% is higher than expected, as the risk is typically thought to be 1-3% for unaffected parents to have an additional child with congenital heart disease (Van der Bom et al., 2011).

#### **4. Natural history and outcome**

The natural history of ccTGA depends largely on the presence of associated defects. Patients under 5 years old who also have VSD, LVOTO, and/or TV abnormalities represent the highest frequency of non-surgical deaths. However patients with isolated ccTGA (no associated lesions) may survive into their 4th and 5th decades (Hoffman, 2009; Presbitero et al., 1995). Many patients will demonstrate one or more complications including heart block, tricuspid regurgitation (TR), and congestive heart failure (CHF). Approximately 2-4% of ccTGA patients have ventricular pre-excitation (Wolff-Parkinson-White syndrome) and should undergo radiofrequency ablation of accessory pathways in cases of symptomatic reentrant tachycardia. Atrial tachycardia such as atrial fibrillation and flutter often occur with increasing age, atrial enlargement, and after surgical repair where suture lines and scars may support focal reentrant circuits. By 45 years of age 67% of ccTGA patients with associated defects will have developed CHF, as shown in Figure 2, whereas only 25% of ccTGA patients without associated lesions will have progressed to CHF by this age (Graham et al., 2000). Prieto et al suggests that outcome is dependent on morphology of the TV (the systemic AV valve), as this was the only predictor of severe regurgitation and RV dysfunction in a cohort of ccTGA patients described after mean follow-up of 20 years.

Fig. 2. Freedom from CHF in group I (associated lesions, n=125) and group II (no significant associated lesions, n=50) as a function of increasing age. (Reprinted from *Journal of the American College of Cardiology*, Vol. 36, No. 1, Long-term outcome in congenitally corrected transposition of the great arteries: A multi-institutional study, pp. 255-261, Copyright 2000 with permission from Elsevier).

The authors concluded that severe TV insufficiency leading to RV dysfunction has the greatest impact on long-term survival in both operated and unoperated patients. In patients who underwent surgical intervention for ccTGA, 20-year survival rate was 90% for patients with competent TVs, whereas survival was only 35% for patients with severe TV insufficiency. Furthermore, patients who were diagnosed with severe TV insufficiency demonstrated a rapid deterioration in clinical status with RV failure occurring on average 5 years after onset of insufficiency (Prieto et al., 1998). Overall natural history in the ccTGA patient without associated defects is promising, as patients may remain relatively asymptomatic through early and mid-adulthood. However the frequent development of complications in the 4th and 5th decades often culminates in the progressive development of RV (systemic) dysfunction and heart failure, requiring aggressive medical management and possible surgical intervention (Presbitero et al., 1995).
